Proteasome inhibitors and methods of using the same

ABSTRACT

The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly or indirectly with proteasome activity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/351,193, filed Feb. 9, 2006, which claims the benefit of U.S.Provisional Application No. 60/652,370, filed Feb. 11, 2005, theentireties of which are incorporated herein.

FIELD OF THE INVENTION

The present invention relates to boronic acid and boronic estercompounds useful as proteasome inhibitors and modulation of apoptosis.

BACKGROUND OF THE INVENTION

The proteasome, (also referred to as multicatalytic protease (MCP),multicatalytic proteinase, multicatalytic proteinase complex,multicatalytic endopeptidase complex, 20S, 26S, or ingensin) is a large,multiprotein complex present in both the cytoplasm and the nucleus ofall eukaryotic cells. It is a highly conserved cellular structure thatis responsible for the ATP-dependent proteolysis of most cellularproteins (Tanaka, Biochem Biophy. Res. Commun., 1998, 247, 537). The 26Sproteasome consists of a 20S core catalytic complex that is capped ateach end by a 19S regulatory subunit. The archaebacterial 20S proteasomecontains fourteen copies of two distinct types of subunits, α and β,which form a cylindrical structure consisting of four stacked rings. Thetop and bottom rings contain seven α-subunits each, while the innerrings contain seven α-subunits. The more complex eukaryotic 20Sproteasome is composed of about 15 distinct 20-30 kDa subunits and ischaracterized by three major activities with respect to peptidesubstrates. For example, the proteasome displays tryptic-,chymotryptic-, and peptidylglutamyl peptide-hydrolytic activities(Rivett, Biochem. J., 1993, 291, 1 and Orlowski, Biochemistry, 1990, 29,10289). Further, the proteasome has a unique active site mechanism whichis believed to utilize a threonine residue as the catalytic nucleophile(Seemuller, et al., Science, 1995, 268, 579).

The 26S proteasome is able to degrade proteins that have been marked bythe addition of ubiquitin molecules. Typically, ubiquitin is attached tothe 1-amino groups of lysines in a multistep process utilizing ATP andE1 (ubiquitin activating) and E2 (ubiquitin-conjugating) enzymes.Multi-ubiquitinated substrate proteins are recognized by the 26Sproteasome and are degraded. The multi-ubiquitin chains are generallyreleased from the complex and ubiquitin is recycled (Goldberg, et al.,Nature, 1992, 357, 375).

Numerous regulatory proteins are substrates for ubiquitin dependentproteolysis. Many of these proteins function as regulators ofphysiological as well as pathophysiological cellular processes.Alterations in proteasome activity have been implicated in a number ofpathologies including neurodegenerative diseases such as Parkinson'sdisease, Alzheimer's disease, as well as occlusion/ischaemia reperfusioninjuries, and aging of the central nervous system.

The ubiquitin-proteasome pathway also plays a role in neoplastic growth.The regulated degradation of proteins such as cyclins, CDK2 inhibitors,and tumor suppressors is believed to be important in cell cycleprogression and mitosis. A known substrate of the proteasome is thetumor suppressor p53 which is involved in several cellular processes(see, e.g., Ko, L. J. Genes Dev., 1996, 10, 1054). Tumor suppressor p53has been shown to induce apoptosis in several haematopoietic cell lines(Oren, M., Semin. Cancer Biol., 1994, 5, 221). Induction of p53 leads tocell growth arrest in the GI phase of the cell cycle as well as celldeath by apoptosis. Tumor suppressor p53 degradation is known to becarried out via the ubiquitin-proteasome pathway, and disrupting p53degradation by inhibition of the proteasome is a possible mode ofinducing apoptosis.

The proteasome is also required for activation of the transcriptionfactor NF-κB by degradation of its inhibitory protein, IκB (Palombella,et al., Cell, 1994, 78, 773). NF-κB has a role in maintaining cellviability through the transcription of inhibitors of apoptosis. Blockadeof NF-κB activity has been demonstrated to make cells more susceptibleto apoptosis.

Several inhibitors of the proteolytic activity of the proteasome havebeen reported. See, for example, Kisselev, et al., Chemistry & Biology,2001, 8, 739. Lactacystin is a Streptomyces metabolite that specificallyinhibits the proteolytic activity of the proteasome complex (Fenteany,et al., Science, 1995, 268, 726). This molecule is capable of inhibitingthe proliferation of several cell types (Fenteany, et al., Proc. Natl.Acad. Sci. USA, 1994, 91, 3358). It has been shown that lactacystinbinds irreversibly, through its β-lactone moiety, to a threonine residuelocated at the amino terminus of the β-subunit of the proteasome.

Peptide aldehydes have been reported to inhibit the chymotrypsin-likeactivity associated with the proteasome (Vinitsky, et al., Biochemistry,1992, 31, 9421; Tsubuki, et al., Biochem. Biophys. Res. Commun., 1993,196, 1195; and Rock, et al., Cell, 1994, 78, 761). Dipeptidyl aldehydeinhibitors that have IC₅₀ values in the 10-100 nM range in vitro (Iqbal,M., et al., J. Med. Chem., 1995, 38, 2276) have also been reported. Aseries of similarly potent in vitro inhibitors from α.-ketocarbonyl andboronic ester derived dipeptides has also been reported (Iqbal, et al.,Bioorg. Med. Chem. Lett., 1996, 6, 287, U.S. Pat. Nos. 5,614,649;5,830,870; 5,990,083; 6,096,778; 6,310,057; U.S. Pat. App. Pub. No.2001/0012854, and WO 99/30707).

N-terminal peptidyl boronic ester and acid compounds have been reportedpreviously (U.S. Pat. Nos. 4,499,082 and 4,537,773; WO 91/13904;Kettner, et al., J. Biol. Chem., 1984, 259(24), 15106). These compoundsare reported to be inhibitors of certain proteolytic enzymes. N-terminaltri-peptide boronic ester and acid compounds have been shown to inhibitthe growth of cancer cells (U.S. Pat. No. 5,106,948). A broad class ofN-terminal tri-peptide boronic ester and acid compounds and analogsthereof has been shown to inhibit renin (U.S. Pat. No. 5,169,841).

Various inhibitors of the peptidase activities of the proteasome havealso been reported. See, e.g., Dick, et al., Biochemistry, 1991, 30,2725; Goldberg, et al., Nature, 1992, 357, 375; Goldberg, Eur. J.Biochem., 1992, 203, 9; Orlowski, Biochemistry, 1990, 29, 10289; Rivett,et al., Archs. Biochem. Biophys., 1989, 218, 1; Rivett, et al., J. Biol.Chem., 1989, 264, 12215; Tanaka, et al., New Biol., 1992, 4, 1;Murakami, et al., Proc. Natl. Acad. Sci. USA, 1986, 83, 7588; Li et al.,Biochemistry, 1991, 30, 9709; Goldberg, Eur. J. Biochem., 1992, 203, 9;and Aoyagi, et al., Proteases and Biological Control, Cold Spring HarborLaboratory Press (1975), pp. 429-454.

Stein et al., U.S. patent application Ser. No. 08/212,909, filed Mar.15, 1994, report peptide aldehydes useful for reducing in an animal boththe rate of loss of muscle mass and the rate of intracellular proteinbreakdown. The compounds are also said to reduce the rate of degradationof p53 protein in an animal. Palombella, et al., WO 95/25533, report theuse of peptide aldehydes to reduce the cellular content and activity ofNF-κB in an animal by contacting cells of the animal with a peptidealdehyde inhibitor of proteasome function or ubiquitin conjugation.Goldberg and Rock, WO 94/17816, report the use of proteasome inhibitorsto inhibit MHC-I antigen presentation. Stein, et al., U.S. Pat. No.5,693,617 report peptidyl aldehyde compounds as proteasome inhibitorsuseful for reducing the rate of degradation of protein in an animal.Inhibition of the 26S and 20S proteasome by indanone derivatives and amethod for inhibiting cell proliferation using indanone derivatives arereported by Lum et al., U.S. Pat. No. 5,834,487. Alpha-ketoamidecompounds useful for treating disorders mediated by 20S proteasome inmammals are reported in Wang et al., U.S. Pat. No. 6,075,150. France, etal., WO 00/64863, report the use of 2,4-diamino-3-hydroxycarboxylic acidderivatives as proteasome inhibitors. Carboxylic acid derivatives asproteasome inhibitors are reported by Yamaguchi et al., EP 1166781.Ditzel, et al., EP 0 995 757 report bivalent inhibitors of theproteasome. 2-Aminobenzylstatine derivatives that inhibit non-covalentlythe chymotrypsin-like activity of the 20S proteasome have been reportedby Garcia-Echeverria, et al., Bioorg. Med. Chem. Lett., 2001, 11, 1317.

Some further proteasome inhibitors can contain boron moieties. Forexample, Drexler et al., WO 00/64467, report a method of selectivelyinducing apoptosis in activated endothelial cells or leukemic cellshaving a high expression level of c-myc by using tetrapeptidic boronatecontaining proteasome inhibitors. Furet et al., WO 02/096933 report2-[[N-(2-amino-3-(heteroaryl oraryl)propionyl)aminoacyl]amino]alkylboronic acids and esters for thetherapeutic treatment of proliferative diseases in warm-blooded animals.U.S. Pat. Nos. 6,083,903; 6,297,217; 5,780,454; 6,066,730; 6,297,217;6,548,668; U.S. Patent Application Pub. No. 2002/0173488; and WO96/13266 report boronic ester and acid compounds and a method forreducing the rate of degradation of proteins. A method for inhibitingviral replication using certain boronic acids and esters is alsoreported in U.S. Pat. No. 6,465,433 and WO 01/02424. Pharmaceuticallyacceptable compositions of boronic acids and novel boronic acidanhydrides and boronate ester compounds are reported by Plamondon, etal., U.S. Patent Application Pub. No. 2002/0188100. A series of di- andtripeptidyl boronic acids are shown to be inhibitors of 20S and 26Sproteasome in Gardner, et al., Biochem. J., 2000, 346, 447.

Other boron-containing peptidyl and related compounds are reported inU.S. Pat. Nos. 5,250,720; 5,242,904; 5,187,157; 5,159,060; 5,106,948;4,963,655; 4,499,082; and WO 89/09225, WO/98/17679, WO 98/22496, WO00/66557, WO 02/059130, WO 03/15706, WO 03/59898, WO 96/12499, WO95/20603, WO 95/09838, WO 94/25051, WO 94/25049, WO 94/04653, WO02/08187, EP 632026, and EP 354522. U.S. patent application Ser. Nos.10/918,664 and 10/918,610, the disclosures of each of which areincorporated herein by reference in their entireties, further reportadditional boron-containing peptidyl-like proteasome inhibitors.

A great interest exists, as evidenced by the above references, in drugswhich can modulate proteasome activity. For example, molecules capableof inhibiting proteasome activity can arrest or delay cancer progressionby interfering with the ordered degradation of cell cycle proteins ortumor suppressors. Accordingly, there is an ongoing need for new and/orimproved inhibitors of proteasome.

SUMMARY OF THE INVENTION

The present invention is directed to novel boronic acid and boronicester compounds useful as proteasome inhibitors and modulation ofapoptosis. The subject invention also comprises methods for inhibitionof multicatalytic protease (“MCP”) associated with certain disorders,including the treatment of muscle wasting disorders.

In one embodiment are provided compounds having Formula (I):

wherein constituent members are defined infra, as well as preferredconstituent members.

In another embodiments, the present invention provides a compound whichis a boronic anhydride of a compound of Formula (I), such as a cyclicboronic anhydride.

In another embodiment the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier.

In another embodiment the present invention provides a method ofinhibiting activity of proteasome comprising contacting a compound ofFormula (I) with the proteasome.

In another embodiment the present invention provides a method oftreating cancer comprising administering to a mammal having orpredisposed to the cancer a therapeutically effective amount of acompound of Formula (I).

In another embodiment the present invention provides a method oftreating cancer comprising administering to a mammal having orpredisposed to the cancer a therapeutically effective amount of acompound of Formula (I), and wherein the cancer is selected from skin,prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue,lung, and smooth muscle tissue.

In another embodiment the present invention provides a method oftreating cancer comprising administering to a mammal having orpredisposed to the cancer a therapeutically effective amount of acompound of Formula (I), and wherein said cancer is selected fromleukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.

In another embodiment the present invention provides a method oftreating cancer comprising administering to a mammal having orpredisposed to the cancer a therapeutically effective amount of acompound of Formula (I) in combination with one or more antitumor oranticancer agent and/or radiotherapy.

In another embodiment the present invention provides a method ofinhibiting activity of transcription factor NF-κB comprising contactingIκB, the inhibitor of transcription factor NF-κB, with a compound ofFormula (I).

In another embodiment, the present invention provides a compound ofFormula (I) for use in therapy.

In another embodiment, the present invention provides use of a compoundof Formula (I) for the manufacture of a medicament for the treatment ofcancer.

These and other features of the compounds will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION

The present invention provides, inter alia, compounds that can inhibitproteasome activity and be used for the treatment of diseases ordisorders related to proteasome activity. Compounds of the inventioninclude compounds of Formula (I):

or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH(OH)CH₃ or —CH₂NR^(1a)R¹;

Hy is a 5- or 6-membered heterocyclic group optionally fused with anaryl or heteroaryl group, wherein said 5- or 6-membered heterocyclicgroup contains at least one ring-forming N atom, and wherein said Hy isoptionally substituted by 1, 2 or 3 R⁴;

R¹ is H, C₁₋₁₀ alkyl, carbocyclyl, heterocyclyl, C₁₋₁₀ alkyl-C(═O)—,C₂₋₁₀ alkenyl-C(═O)—, C₂₋₁₀ alkynyl-C(═O)—, carbocyclyl-C(═O)—,heterocyclyl-C(═O)—, carbocyclylalkyl-C(═O)—, heterocyclylalkyl-C(═O)—,C₁₋₁₀ alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocyclyl-S(═O)₂—,carbocyclylalkyl-S(═O)₂—, heterocyclylalkyl-S(═O)₂—, C₁-C₁₀alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocyclyl-NHC(═O)—,carbocyclylalkyl-NHC(═O)—, heterocyclylalkyl-NHC(═O)—, C₁-C₁₀alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocyclyl-OC(═O)—,carbocyclylalkyl-OC(═O)—, heterocyclylalkyl-OC(═O)—, C₁₋₁₀alkyl-NH—C(═O)—NHS(═O)₂—, carbocyclyl-NH—C(═O)—NHS(═O)₂—,heterocyclyl-NH—C(═O)—NHS(═O)₂—, C₁₋₁₀ alkyl-S(═O)₂—NH—C(═O)—,carbocyclyl-S(═O)₂—NH—C(═O)—, heterocyclyl-S(═O)₂—NH—C(═O)—, or an aminoprotecting group; wherein R¹ is optionally substituted with 1, 2 or 3substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, F,Cl, Br, I, C₁₋₄ haloalkyl, —NH₂, —NHR², —N(R²)₂, —N₃, —NO₂, —CN, —CNO,—CNS, —C(═O)OR², —C(═O)R², —OC(═O)R², —N(R²)C(═O)R², —N(R²)C(═O)OR²,—C(═O)N(R²)₂, ureido, —OR², —SR², —S(═O)—(C₁₋₆ alkyl), —S(═O)₂—(C₁₋₆alkyl), —S(═O)-aryl, —S(═O)₂-aryl, —S(═O)₂—N(R²)₂; carbocyclyloptionally substituted with 1, 2, 3, 4 or 5 R³; and heterocyclyloptionally substituted with 1, 2, 3, 4, or 5 R³;

R^(1a) is H. Alternatively, R^(1a) and R¹ together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocyclylgroup optionally substituted with 1, 2, or 3 R³;

R² is, independently, H or C₁₋₆ alkyl;

alternatively, two R² may be combined, together with the N atom to whichthey are attached, to form a 5-, 6- or 7-membered heterocyclic group;

R³ is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—;

R⁴ is, independently, selected from C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀alkynyl, —OR^(4a), —SR^(4a), —CN, halo, haloalkyl, —NH₂, —NH(alkyl),—N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —COOH, —C(═O)O-alkyl,—C(═O)alkyl, —C(O)H, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,—S(═O)₂-aryl, carbocyclyl optionally substituted with 1, 2 or 3 R⁵, andheterocyclyl optionally substituted with 1, 2 or 3 R⁵;

R^(4a) is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, carbocyclylor heterocyclyl;

R⁵ is, independently, selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—;

with the proviso that when Z is —CH(OH)CH₃ and Q is

then Hy is other than

In some embodiments, Q is boronic acid (B(OH)₂) or a cyclic boronicester wherein said cyclic boronic ester contains from 6 to 10 carbonatoms and contains at least one cycloalkyl moiety.

In some embodiments, Q is B(OH)₂ or pinanediol boronic ester.

In some embodiments, Q is pinanediol boronic ester.

In some embodiments, Z is —CH(OH)CH₃.

In some embodiments, Z is —CH₂NR^(1a)R¹.

In some embodiments, Z is —CH₂NHR¹.

In some embodiments, Z is —CH₂NHR¹ and R¹ is carbocyclyl-C(═O)— orcarbocyclyl-S(═O)₂—, each optionally substituted with 1, 2 or 3substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, F,Cl, Br, I, C₁₋₄ haloalkyl, —NH₂, —NHR², —N(R²)₂, —N₃, —NO₂, —CN, —CNO,—CNS, —C(═O)OR², —C(═O)R², —OC(═O)R², —N(R²)C(═O)R², —N(R²)C(═O)OR²,—C(═O)N(R²)₂, ureido, —OR², —SR², —S(═O)—(C₁₋₆ alkyl), —S(═O)₂—(C₁₋₆alkyl), —S(═O)-aryl, —S(═O)₂-aryl, —S(═O)₂—N(R²)₂; carbocyclyloptionally substituted with 1, 2, 3, 4 or 5 R³; and heterocyclyloptionally substituted with 1, 2, 3, 4, or 5 R³.

In some embodiments, Z is —CH₂NHR¹ and R¹ is aryl-C(═O)— oraryl-S(═O)₂—, each optionally substituted with 1, 2 or 3 substituentsselected from C₁₋₆ alkyl, F, Cl, Br, I, C₁₋₄ haloalkyl, carbocyclyloptionally substituted with 1, 2, 3, 4 or 5 R³ and heterocyclyloptionally substituted with 1, 2, 3, 4, or 5 R³.

In some embodiments, Z is —CH₂NHR¹ and R¹ is phenyl-C(═O)— orphenyl-S(═O)₂—, each optionally substituted with C₁₋₄ alkyl, F, Cl, Br,I, or aryl.

In some embodiments, R¹ is aryl-C(═O)— or aryl-S(═O)₂—, each optionallysubstituted with 1, 2 or 3 substituents selected from C₁₋₆ alkyl, F, Cl,Br, I, C₁₋₄ haloalkyl, carbocyclyl optionally substituted with 1, 2, 3,4 or 5 R³ and heterocyclyl optionally substituted with 1, 2, 3, 4, or 5R³.

In some embodiments, R¹ is aryl-C(═O)— optionally substituted with 1, 2or 3 substituents selected from C₁₋₆ alkyl, F, Cl, Br, I, and C₁₋₄haloalkyl.

In some embodiments, R¹ is phenyl-C(═O)— optionally substituted with 1,2 or 3 substituents selected from C₁₋₆ alkyl, F, Cl, Br, I, and C₁₋₄haloalkyl.

In some embodiments, R¹ is —CO-(4-methylphenyl).

In some embodiments, R¹ is optionally substituted with 1 or 2substituents.

In some embodiments, R¹ is optionally substituted with 1 substituent.

In some embodiments, R¹ is substituted with 1 substituent.

In some embodiments, R¹ is substituted with C₁₋₆ alkyl.

In some embodiments, R¹ is substituted with methyl.

In some embodiments, Hy is pyridyl, N-oxopyridyl, pyrimidinyl,pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl,quinolinyl, isoquinolinyl, quinoxalinyl, indolyl, quinazolinyl,benzoimidazolyl, benzothiazolyl, or benzoxazolyl, each optionallysubstituted by 1, 2 or 3 R⁴.

In some embodiments, Hy is pyridyl, N-oxopyridyl, pyrimidinyl,pyrazinyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl,quinoxalinyl, or indolyl, each optionally substituted by 1, 2 or 3 R⁴.

In some embodiments, Hy is pyridyl, N-oxopyridyl, pyrimidinyl,pyrazinyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl,quinoxalinyl, or indolyl, each optionally substituted by 1 or 2 C₁₋₈alkyl, carbocyclyl optionally substituted with 1, 2 or 3 R⁵, orheterocyclyl optionally substituted with 1, 2 or 3 R⁵.

In some embodiments, Hy is pyridyl, N-oxopyridyl, pyrimidinyl,pyrazinyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl,quinoxalinyl, or indolyl, each optionally substituted by 1 or 2 methyl,ethyl, propyl, butyl, aryl optionally substituted with 1, 2 or 3 R⁵, orheteroaryl optionally substituted with 1, 2 or 3 R⁵.

In some embodiments, Hy is pyridyl, pyrimidinyl, pyrazinyl, thiazolyl,pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or indolyl, eachoptionally substituted by 1 or 2 methyl, ethyl, propyl, butyl, aryloptionally substituted with 1, 2 or 3 R⁵, or heteroaryl optionallysubstituted with 1, 2 or 3 R⁵.

In some embodiments, Hy is pyrazine substituted by at least 1 or 2 R⁴,unsubstituted pyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2R⁴, pyridin-4-yl optionally substituted by 1 or 2 R⁴, N-oxo-pyridinyloptionally substituted by 1 or 2 R⁴, pyrimidinyl optionally substitutedby 1 or 2 R⁴, imidazolyl optionally substituted by 1 or 2 R⁴, thiazolyloptionally substituted by 1 or 2 R⁴, oxazolyl optionally substituted by1 or 2 R⁴, pyrrolyl optionally substituted by 1 or 2 R⁴, pyrazolyloptionally substituted by 1 or 2 R⁴, quinolinyl optionally substitutedby 1 or 2 R⁴, isoquinolinyl optionally substituted by 1 or 2 R⁴,quinoxalinyl optionally substituted by 1 or 2 R⁴, indolyl optionallysubstituted by 1 or 2 R⁴, quinazolinyl optionally substituted by 1 or 2R⁴, benzoimidazolyl optionally substituted by 1 or 2 R⁴, benzothiazolyloptionally substituted by 1 or 2 R⁴, or benzoxazolyl optionallysubstituted by 1 or 2 R⁴.

In some embodiments, Hy is pyrazine substituted by at least 1 or 2 R⁴,unsubstituted pyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2R⁴, pyridin-4-yl optionally substituted by 1 or 2 R⁴, N-oxo-pyridinyloptionally substituted by 1 or 2 R⁴, pyrimidinyl optionally substitutedby 1 or 2 R⁴, imidazolyl optionally substituted by 1 or 2 R⁴, thiazolyloptionally substituted by 1 or 2 R⁴, oxazolyl optionally substituted by1 or 2 R⁴, pyrrolyl optionally substituted by 1 or 2 R⁴, pyrazolyloptionally substituted by 1 or 2 R⁴, quinolinyl optionally substitutedby 1 or 2 R⁴, isoquinolinyl optionally substituted by 1 or 2 R⁴,quinoxalinyl optionally substituted by 1 or 2 R⁴, indolyl optionallysubstituted by 1 or 2 R⁴, quinazolinyl optionally substituted by 1 or 2R⁴, benzoimidazolyl optionally substituted by 1 or 2 R⁴, benzothiazolyloptionally substituted by 1 or 2 R⁴, or benzoxazolyl optionallysubstituted by 1 or 2 R⁴, wherein R⁴ is C₁₋₆ alkyl, aryl orheterocyclyl.

In some embodiments, Hy is pyrazine substituted by at least 1 or 2 R⁴,unsubstituted pyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2R⁴, pyridin-4-yl optionally substituted by 1 or 2 R⁴, N-oxo-pyridinyloptionally substituted by 1 or 2 R⁴, pyrimidinyl optionally substitutedby 1 or 2 R⁴, imidazolyl optionally substituted by 1 or 2 R⁴, thiazolyloptionally substituted by 1 or 2 R⁴, pyrazolyl optionally substituted by1 or 2 R⁴, quinolinyl optionally substituted by 1 or 2 R⁴, isoquinolinyloptionally substituted by 1 or 2 R⁴, quinoxalinyl optionally substitutedby 1 or 2 R⁴, or indolyl optionally substituted by 1 or 2 R⁴.

In some embodiments, Hy is pyrazine substituted by at least 1 or 2 R⁴,unsubstituted pyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2R⁴, pyridin-4-yl optionally substituted by 1 or 2 R⁴, N-oxo-pyridinyloptionally substituted by 1 or 2 R⁴, pyrimidinyl optionally substitutedby 1 or 2 R⁴, imidazolyl optionally substituted by 1 or 2 R⁴, thiazolyloptionally substituted by 1 or 2 R⁴, pyrazolyl optionally substituted by1 or 2 R⁴, quinolinyl optionally substituted by 1 or 2 R⁴, isoquinolinyloptionally substituted by 1 or 2 R⁴, quinoxalinyl optionally substitutedby 1 or 2 R⁴, or indolyl optionally substituted by 1 or 2 R⁴, wherein R⁴is C₁₋₆ alkyl, aryl or heterocyclyl.

In some embodiments, Hy is pyrazine substituted by at least 1 or 2 R⁴,unsubstituted pyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2R⁴, pyridin-4-yl optionally substituted by 1 or 2 R⁴, pyrimidinyloptionally substituted by 1 or 2 R⁴, imidazolyl optionally substitutedby 1 or 2 R⁴, thiazolyl optionally substituted by 1 or 2 R⁴, pyrazolyloptionally substituted by 1 or 2 R⁴, quinolinyl optionally substitutedby 1 or 2 R⁴, isoquinolinyl optionally substituted by 1 or 2 R⁴,quinoxalinyl optionally substituted by 1 or 2 R⁴, or indolyl optionallysubstituted by 1 or 2 R⁴, wherein R⁴ is C₁₋₆ alkyl, aryl orheterocyclyl.

In some embodiments, Hy is selected from:

In some embodiments, R^(1a) is H.

In some embodiments, R^(B) is H.

In some embodiments, R⁴ is unsubstituted.

In some embodiments, R⁴ is methyl, ethyl, propyl, butyl, aryl optionallysubstituted with 1, 2 or 3 R⁵, or heteroaryl optionally substituted with1, 2 or 3 R⁵.

In some embodiments, R⁴ is C₁₋₆ alkyl, aryl or heterocyclyl.

In some embodiments, R⁴ is methyl, butyl, phenyl, thienyl, ormorpholino.

In some embodiments:

Z is —CH(OH)CH₃; and

Hy is a 5- or 6-membered heterocyclic group optionally fused with anaryl or heteroaryl group, wherein said 5- or 6-membered heterocyclicgroup contains at least one ring-forming N atom, and wherein said Hy isoptionally substituted by 1, 2 or 3 R⁴.

In some embodiments:

Z is —CH(OH)CH₃; and

Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl,thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl,quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, orbenzoxazolyl, each optionally substituted by 1, 2 or 3 R⁴.

In some embodiments:

Z is —CH₂NHR¹;

Hy is a 5- or 6-membered heterocyclic group optionally fused with anaryl or heteroaryl group, wherein said 5- or 6-membered heterocyclicgroup contains at least one ring-forming N atom, and wherein said Hy isoptionally substituted by 1, 2 or 3 R⁴; and

R¹ is carbocyclyl-C(═O)— or carbocyclyl-S(═O)₂—, each optionallysubstituted with 1, 2 or 3 substituents selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, F, Cl, Br, I, C₁₋₄ haloalkyl, —NH₂, —NHR²,—N(R²)₂, —N₃, —NO₂, —CN, —CNO, —CNS, —C(═O)OR², —C(═O)R², —OC(═O)R²,—N(R²)C(═O)R², —N(R²)C(═O)OR², —C(═O)N(R²)₂, ureido, —OR², —SR²,—S(═O)—(C₁₋₆ alkyl), —S(═O)₂—(C₁₋₆ alkyl), —S(═O)-aryl, —S(═O)₂-aryl,—S(═O)₂—N(R²)₂; carbocyclyl optionally substituted with 1, 2, 3, 4 or 5R³; and heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 R³.

In some embodiments:

Z is —CH₂NHR¹;

Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl,thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl,quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, orbenzoxazolyl, each optionally substituted by 1, 2 or 3 R⁴; and

R¹ is carbocyclyl-C(═O)— or carbocyclyl-S(═O)₂—, each optionallysubstituted with 1, 2 or 3 substituents selected from C₁₋₆ alkyl, F, Cl,Br, I, C₁₋₄ haloalkyl, carbocyclyl optionally substituted with 1, 2, 3,4 or 5 R³, and heterocyclyl optionally substituted with 1, 2, 3, 4, or 5R³.

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH(OH)CH₃ or —CH₂NHR¹;

Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl,thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl,quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, orbenzoxazolyl, each optionally substituted by 1, 2 or 3 R⁴;

R¹ is carbocyclyl-C(═O)— or heterocyclyl-C(═O)—, each optionallysubstituted with 1, 2 or 3 R³;

R³ is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—;

R⁴ is, independently, selected from C₁₋₆ alkyl, aryl and heterocyclyl;

with the proviso that when Z is —CH(OH)CH₃ and Q is

then Hy is other than

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH(OH)CH₃ or —CH₂NHR¹;

Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl,thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl,quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, orbenzoxazolyl, each optionally substituted by 1, 2 or 3 C₁₋₆ alkyl, arylor heterocyclyl;

R¹ is carbocyclyl-C(═O)— or heterocyclyl-C(═O)—, each optionallysubstituted with 1, 2 or 3 R³;

R³ is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—;

R⁴ is, independently, selected from C₁₋₆ alkyl, aryl and heterocyclyl;

with the proviso that when Z is —CH(OH)CH₃ and Q is

then Hy is other than

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH(OH)CH₃ or —CH₂NHR¹;

Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl,thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl,quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, orbenzoxazolyl, each optionally substituted by 1, 2 or 3 C1-6 alkyl,phenyl, thienyl or morpholino;

R¹ is carbocyclyl-C(═O)— or heterocyclyl-C(═O)—, each optionallysubstituted with 1, 2 or 3 R³;

R³ is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—;

R⁴ is, independently, selected from C₁₋₆ alkyl, aryl and heterocyclyl;

with the proviso that when Z is —CH(OH)CH₃ and Q is

then Hy is other than

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH(OH)CH₃ or —CH₂NHR¹;

Hy is selected from

R¹ is carbocyclyl-C(═O)— or heterocyclyl-C(═O)—, each optionallysubstituted with 1, 2 or 3 R³; and

R³ is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—.

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH(OH)CH₃ or —CH₂NHR¹;

Hy is selected from

R¹ is —CO-(4-methylphenyl).

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OH)₂ or pinanediol boronic ester;

Z is —CH(OH)CH₃ or —CH₂NHR¹;

Hy is selected from

R¹ is —CO-(4-methylphenyl).

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH(OH)CH₃;

Hy is a 5- or 6-membered heterocyclic group optionally fused with anaryl or heteroaryl group, wherein said 5- or 6-membered heterocyclicgroup contains at least one ring-forming N atom, and wherein said Hy isoptionally substituted by 1, 2 or 3 R⁴;

R^(B) is, independently, selected from C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀alkynyl, —OR^(4a), SR^(4a), —CN, halo, haloalkyl, —NH₂, —NH(alkyl),—N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —COOH, —C(═O)O-alkyl,—C(═O)alkyl, —C(O)H, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,—S(═O)₂-aryl, carbocyclyl optionally substituted with 1, 2 or 3 R⁵, andheterocyclyl optionally substituted with 1, 2 or 3 R⁵;

R^(4a) is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, carbocyclylor heterocyclyl;

R⁵ is, independently, selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—;

with the proviso that when Q is

then Hy is other than

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH(OH)CH₃;

Hy is pyrazine substituted by at least 1 or 2 R⁴, unsubstitutedpyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2 R⁴,pyridin-4-yl optionally substituted by 1 or 2 R⁴, N-oxo-pyridinyloptionally substituted by 1 or 2 R⁴, pyrimidinyl optionally substitutedby 1 or 2 R⁴, imidazolyl optionally substituted by 1 or 2 R⁴, thiazolyloptionally substituted by 1 or 2 R⁴, oxazolyl optionally substituted by1 or 2 R⁴, pyrrolyl optionally substituted by 1 or 2 R⁴, pyrazolyloptionally substituted by 1 or 2 R⁴, quinolinyl optionally substitutedby 1 or 2 R⁴, isoquinolinyl optionally substituted by 1 or 2 R⁴,quinoxalinyl optionally substituted by 1 or 2 R⁴, indolyl optionallysubstituted by 1 or 2 R⁴, quinazolinyl optionally substituted by 1 or 2R⁴, benzoimidazolyl optionally substituted by 1 or 2 R⁴, benzothiazolyloptionally substituted by 1 or 2 R⁴, or benzoxazolyl optionallysubstituted by 1 or 2 R⁴;

R⁴ is, independently, selected from C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀alkynyl, —OR^(4a), —SR^(4a), —CN, halo, haloalkyl, —NH₂, —NH(alkyl),—N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —COOH, —C(═O)O-alkyl,—C(═O)alkyl, —C(O)H, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,—S(═O)₂-aryl, carbocyclyl optionally substituted with 1, 2 or 3 R⁵, andheterocyclyl optionally substituted with 1, 2 or 3 R⁵;

R^(4a) is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, carbocyclylor heterocyclyl; and

R⁵ is, independently, selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—.

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH(OH)CH₃;

Hy is pyrazine substituted by at least 1 or 2 R⁴, unsubstitutedpyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2 R⁴,pyridin-4-yl optionally substituted by 1 or 2 R⁴, N-oxo-pyridinyloptionally substituted by 1 or 2 R⁴, pyrimidinyl optionally substitutedby 1 or 2 R⁴, imidazolyl optionally substituted by 1 or 2 R⁴, thiazolyloptionally substituted by 1 or 2 R⁴, pyrazolyl optionally substituted by1 or 2 R⁴, quinolinyl optionally substituted by 1 or 2 R⁴, isoquinolinyloptionally substituted by 1 or 2 R⁴, quinoxalinyl optionally substitutedby 1 or 2 R⁴, or indolyl optionally substituted by 1 or 2 R⁴;

R⁴ is, independently, selected from C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀alkynyl, —OR^(4a), —SR^(4a), —CN, halo, haloalkyl, —NH₂, —NH(alkyl),—N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —COOH, —C(═O)O-alkyl,—C(═O)alkyl, —C(O)H, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,—S(═O)₂-aryl, carbocyclyl optionally substituted with 1, 2 or 3 R⁵, andheterocyclyl optionally substituted with 1, 2 or 3 R⁵;

R^(4a) is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, carbocyclylor heterocyclyl; and

R⁵ is, independently, selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—.

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH(OH)CH₃; and

Hy is selected from

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OH)₂ or pinanediol boronic ester;

Z is —CH(OH)CH₃; and

Hy is selected from

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH₂NR^(1a)R¹;

Hy is a 5- or 6-membered heterocyclic group optionally fused with anaryl or heteroaryl group, wherein said 5- or 6-membered heterocyclicgroup contains at least one ring-forming N atom, and wherein said Hy isoptionally substituted by 1, 2 or 3 R⁴;

R¹ is H, C₁₋₁₀ alkyl, carbocyclyl, heterocyclyl, C₁₋₁₀ alkyl-C(═O)—,C₂₋₁₀ alkenyl-C(═O)—, C₂₋₁₀ alkynyl-C(═O)—, carbocyclyl-C(═O)—,heterocyclyl-C(═O)—, carbocyclylalkyl-C(═O)—, heterocyclylalkyl-C(═O)—,C₁₋₁₀ alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocyclyl-S(═O)₂—,carbocyclylalkyl-S(═O)₂—, heterocyclylalkyl-S(═O)₂—, C₁-C₁₀alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocyclyl-NHC(═O)—,carbocyclylalkyl-NHC(═O)—, heterocyclylalkyl-NHC(═O)—, C₁-C₁₀alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocyclyl-OC(═O)—,carbocyclylalkyl-OC(═O)—, heterocyclylalkyl-OC(═O)—, C₁₋₁₀alkyl-NH—C(═O)—NHS(═O)₂—, carbocyclyl-NH—C(═O)—NHS(═O)₂—,heterocyclyl-NH—C(═O)—NHS(═O)₂—, C₁₋₁₀ alkyl-S(═O)₂—NH—C(═O)—,carbocyclyl-S(═O)₂—NH—C(═O)—, heterocyclyl-S(═O)₂—NH—C(═O)—, or an aminoprotecting group; wherein R¹ is optionally substituted with 1, 2 or 3substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, F,Cl, Br, I, C₁₋₄ haloalkyl, —NH₂, —NHR², —N(R²)₂, —N₃, —NO₂, —CN, —CNO,—CNS, —C(═O)OR², —C(═O)R², —OC(═O)R², —N(R²)C(═O)R², —N(R²)C(═O)OR²,—C(═O)N(R²)₂, ureido, —OR², —SR², —S(═O)—(C₁₋₆ alkyl), —S(═O)₂—(C₁₋₆alkyl), —S(═O)-aryl, —S(═O)₂-aryl, —S(═O)₂—N(R²)₂; carbocyclyloptionally substituted with 1, 2, 3, 4 or 5 R³; and heterocyclyloptionally substituted with 1, 2, 3, 4, or 5 R³;

R^(1a) is H. Alternatively, R^(1a) and R¹ together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocyclylgroup optionally substituted with 1, 2, or 3 R³;

R² is, independently, H or C₁₋₆ alkyl;

alternatively, two R² may be combined, together with the N atom to whichthey are attached, to form a 5-, 6- or 7-membered heterocyclic group;

R³ is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—;

R⁴ is, independently, selected from C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀alkynyl, —OR^(4a), —SR^(4a), —CN, halo, haloalkyl, —NH₂, —NH(alkyl),—N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —COOH, —C(═O)O-alkyl,—C(═O)alkyl, —C(O)H, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,—S(═O)₂-aryl, carbocyclyl optionally substituted with 1, 2 or 3 R⁵, andheterocyclyl optionally substituted with 1, 2 or 3 R⁵;

R^(4a) is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, carbocyclylor heterocyclyl; and

R⁵ is, independently, selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—.

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH₂NR^(1a)R¹;

Hy is pyrazine substituted by at least 1 or 2 R⁴, pyridinyl optionallysubstituted by 1 or 2 R⁴, N-oxo-pyridinyl optionally substituted by 1 or2 R⁴, pyrimidinyl optionally substituted by 1 or 2 R⁴, imidazolyloptionally substituted by 1 or 2 R⁴, thiazolyl optionally substituted by1 or 2 R⁴, oxazolyl optionally substituted by 1 or 2 R⁴, pyrrolyloptionally substituted by 1 or 2 R⁴, pyrazolyl optionally substituted by1 or 2 R⁴, quinolinyl optionally substituted by 1 or 2 R⁴, isoquinolinyloptionally substituted by 1 or 2 R⁴, quinoxalinyl optionally substitutedby 1 or 2 R⁴, indolyl optionally substituted by 1 or 2 R⁴, quinazolinyloptionally substituted by 1 or 2 R⁴, benzoimidazolyl optionallysubstituted by 1 or 2 R⁴, benzothiazolyl optionally substituted by 1 or2 R⁴, or benzoxazolyl optionally substituted by 1 or 2 R⁴;

R¹ is H, C₁₋₁₀ alkyl, carbocyclyl, heterocyclyl, C₁₋₁₀ alkyl-C(═O)—,C₂₋₁₀ alkenyl-C(═O)—, C₂₋₁₀ alkynyl-C(═O)—, carbocyclyl-C(═O)—,heterocyclyl-C(═O)—, carbocyclylalkyl-C(═O)—, heterocyclylalkyl-C(═O)—,C₁₋₁₀ alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocyclyl-S(═O)₂—,carbocyclylalkyl-S(═O)₂—, heterocyclylalkyl-S(═O)₂—, C₁-C₁₀alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocyclyl-NHC(═O)—,carbocyclylalkyl-NHC(═O)—, heterocyclylalkyl-NHC(═O)—, C₁-C₁₀alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocyclyl-OC(═O)—,carbocyclylalkyl-OC(═O)—, heterocyclylalkyl-OC(═O)—, C₁₋₁₀alkyl-NH—C(═O)—NHS(═O)₂—, carbocyclyl-NH—C(═O)—NHS(═O)₂—,heterocyclyl-NH—C(═O)—NHS(═O)₂—, C₁₋₁₀ alkyl-S(═O)₂—NH—C(═O)—,carbocyclyl-S(═O)₂—NH—C(═O)—, heterocyclyl-S(═O)₂—NH—C(═O)—, or an aminoprotecting group; wherein R¹ is optionally substituted with 1, 2 or 3substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, F,Cl, Br, I, C₁₋₄ haloalkyl, —NH₂, —NHR², —N(R²)₂, —N₃, —NO₂, —CN, —CNO,—CNS, —C(═O)OR², —C(═O)R², —OC(═O)R², —N(R²)C(═O)R², —N(R²)C(═O)OR²,—C(═O)N(R²)₂, ureido, —OR², —SR², —S(═O)—(C₁₋₆ alkyl), —S(═O)₂—(C₁₋₆alkyl), —S(═O)-aryl, —S(═O)₂-aryl, —S(═O)₂—N(R²)₂; carbocyclyloptionally substituted with 1, 2, 3, 4 or 5 R³; and heterocyclyloptionally substituted with 1, 2, 3, 4, or 5 R³;

R^(1a) is H. Alternatively, R^(1a) and R¹ together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocyclylgroup optionally substituted with 1, 2, or 3 R³;

R² is, independently, H or C₁₋₆ alkyl;

alternatively, two R² may be combined, together with the N atom to whichthey are attached, to form a 5-, 6- or 7-membered heterocyclic group;

R³ is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—;

R⁴ is, independently, selected from C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀alkynyl, —OR^(4a), SR^(4a), —CN, halo, haloalkyl, —NH₂, —NH(alkyl),—N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —COOH, —C(═O)O-alkyl,—C(═O)alkyl, —C(O)H, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,—S(═O)₂-aryl, carbocyclyl optionally substituted with 1, 2 or 3 R⁵, andheterocyclyl optionally substituted with 1, 2 or 3 R⁵;

R^(4a) is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, carbocyclylor heterocyclyl; and

R⁵ is, independently, selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—.

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH₂NR^(1a)R¹;

Hy is selected from

R¹ is H, C₁₋₁₀ alkyl, carbocyclyl, heterocyclyl, C₁₋₁₀ alkyl-C(═O)—,C₂₋₁₀ alkenyl-C(═O)—, C₂₋₁₀ alkynyl-C(═O)—, carbocyclyl-C(═O)—,heterocyclyl-C(═O)—, carbocyclylalkyl-C(═O)—, heterocyclylalkyl-C(═O)—,C₁₋₁₀ alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocyclyl-S(═O)₂—,carbocyclylalkyl-S(═O)₂—, heterocyclylalkyl-S(═O)₂—, C₁-C₁₀alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocyclyl-NHC(═O)—,carbocyclylalkyl-NHC(═O)—, heterocyclylalkyl-NHC(═O)—, C₁-C₁₀alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocyclyl-OC(═O)—,carbocyclylalkyl-OC(═O)—, heterocyclylalkyl-OC(═O)—, C₁₋₁₀alkyl-NH—C(═O)—NHS(═O)₂—, carbocyclyl-NH—C(═O)—NHS(═O)₂—,heterocyclyl-NH—C(═O)—NHS(═O)₂—, C₁₋₁₀ alkyl-S(═O)₂—NH—C(═O)—,carbocyclyl-S(═O)₂—NH—C(═O)—, heterocyclyl-S(═O)₂—NH—C(═O)—, or an aminoprotecting group; wherein R¹ is optionally substituted with 1, 2 or 3substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, F,Cl, Br, I, C₁₋₄ haloalkyl, —NH₂, —NHR², —N(R²)₂, —N₃, —NO₂, —CN, —CNO,—CNS, —C(═O)OR², —C(═O)R², —OC(═O)R², —N(R²)C(═O)R², —N(R²)C(═O)OR²,—C(═O)N(R²)₂, ureido, —OR², —SR², —S(═O)—(C₁₋₆ alkyl), —S(═O)₂—(C₁₋₆alkyl), —S(═O)-aryl, —S(═O)₂-aryl, —S(═O)₂—N(R²)₂; carbocyclyloptionally substituted with 1, 2, 3, 4 or 5 R³; and heterocyclyloptionally substituted with 1, 2, 3, 4, or 5 R³;

R^(1a) is H. Alternatively, R^(1a) and R¹ together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocyclylgroup optionally substituted with 1, 2, or 3 R³;

R² is, independently, H or C₁₋₆ alkyl;

alternatively, two R² may be combined, together with the N atom to whichthey are attached, to form a 5-, 6- or 7-membered heterocyclic group;and

R³ is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—.

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH₂NHR¹;

Hy is selected from

R¹ is H, C₁₋₁₀ alkyl, carbocyclyl, heterocyclyl, C₁₋₁₀ alkyl-C(═O)—,C₂₋₁₀ alkenyl-C(═O)—, C₂₋₁₀ alkynyl-C(═O)—, carbocyclyl-C(═O)—,heterocyclyl-C(═O)—, carbocyclylalkyl-C(═O)—, heterocyclylalkyl-C(═O)—,C₁₋₁₀ alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocyclyl-S(═O)₂—,carbocyclylalkyl-S(═O)₂—, heterocyclylalkyl-S(═O)₂—, C₁-C₁₀alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocyclyl-NHC(═O)—,carbocyclylalkyl-NHC(═O)—, heterocyclylalkyl-NHC(═O)—, C₁-C₁₀alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocyclyl-OC(═O)—,carbocyclylalkyl-OC(═O)—, heterocyclylalkyl-OC(═O)—, C₁₋₁₀alkyl-NH—C(═O)—NHS(═O)₂—, carbocyclyl-NH—C(═O)—NHS(═O)₂—,heterocyclyl-NH—C(═O)—NHS(═O)₂—, C₁₋₁₀ alkyl-S(═O)₂—NH—C(═O)—,carbocyclyl-S(═O)₂—NH—C(═O)—, heterocyclyl-S(═O)₂—NH—C(═O)—, or an aminoprotecting group; wherein R¹ is optionally substituted with 1, 2 or 3substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, F,Cl, Br, I, C₁₋₄ haloalkyl, —NH₂, —NHR², —N(R²)₂, —N₃, —NO₂, —CN, —CNO,—CNS, —C(═O)OR², —C(═O)R², —OC(═O)R², —N(R²)C(═O)R², —N(R²)C(═O)OR²,—C(═O)N(R²)₂, ureido, —OR², —SR², —S(═O)—(C₁₋₆ alkyl), —S(═O)₂—(C₁₋₆alkyl), —S(═O)-aryl, —S(═O)₂-aryl, —S(═O)₂—N(R²)₂; carbocyclyloptionally substituted with 1, 2, 3, 4 or 5 R³; and heterocyclyloptionally substituted with 1, 2, 3, 4, or 5 R³;

R² is, independently, H or C₁₋₆ alkyl;

alternatively, two R² may be combined, together with the N atom to whichthey are attached, to form a 5-, 6- or 7-membered heterocyclic group;and

R³ is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—.

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH₂NHR¹;

Hy is selected from

R¹ is carbocyclyl-C(═O)—, heterocyclyl-C(═O)—, wherein R¹ is optionallysubstituted with 1, 2 or 3 substituents selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, F, Cl, Br, I, C₁₋₄ haloalkyl, —NH₂, —NHR²,—N(R²)₂, —N₃, —NO₂, —CN, —CNO, —CNS, —C(═O)OR², —C(═O)R², —OC(═O)R²,—N(R²)C(═O)R², —N(R²)C(═O)OR², —C(═O)N(R²)₂, ureido, —OR², —SR²,—S(═O)—(C₁₋₆ alkyl), —S(═O)₂—(C₁₋₆ alkyl), —S(═O)-aryl, —S(═O)₂-aryl,—S(═O)₂—N(R²)₂; carbocyclyl optionally substituted with 1, 2, 3, 4 or 5R³; and heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 R³;

R² is, independently, H or C₁₋₆ alkyl;

alternatively, two R² may be combined, together with the N atom to whichthey are attached, to form a 5-, 6- or 7-membered heterocyclic group;and

R³ is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—.

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH₂NHR¹;

Hy is selected from

R¹ is aryl-C(═O)—, wherein R¹ is optionally substituted with 1 or 2substituents selected from C₁₋₆ alkyl, F, Cl, Br, I, and C₁₋₄ haloalkyl.

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH₂NHR¹;

Hy is selected from

R¹ is —CO-(4-methylphenyl).

In some embodiments, compounds of the invention include compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OH)₂ pinanediol boronic ester;

Z is —CH₂NHR¹;

Hy is selected from

R¹ is —CO-(4-methylphenyl).

In some embodiments compounds of the invention include compounds ofFormula (I):

or pharmaceutically acceptable salt forms thereof, wherein:

Q is —B(OR^(B))₂, boronic acid, or a cyclic boronic ester wherein saidcyclic boronic ester contains from 2 to 20 carbon atoms, and,optionally, a heteroatom which can be N, S, or O;

R^(B) is, independently, H, C₁₋₄ alkyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl;

Z is —CH(OH)CH₃ or —CH₂NR^(1a)R¹;

Hy is a 5- or 6-membered heterocyclic group optionally fused with anaryl or heteroaryl group, wherein said 5- or 6-membered heterocyclicgroup contains at least one ring-forming N atom, and wherein said Hy isoptionally substituted by 1, 2 or 3 R⁴;

R¹ is H, C₁₋₁₀ alkyl, carbocyclyl, heterocyclyl, C₁₋₁₀ alkyl-C(═O)—,C₂₋₁₀ alkenyl-C(═O)—, C₂₋₁₀ alkynyl-C(═O)—, carbocyclyl-C(═O)—,heterocyclyl-C(═O)—, carbocyclylalkyl-C(═O)—, heterocyclylalkyl-C(═O)—,C₁₋₁₀ alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocyclyl-S(═O)₂—,carbocyclylalkyl-S(═O)₂—, heterocyclylalkyl-S(═O)₂—, C₁-C₁₀alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocyclyl-NHC(═O)—,carbocyclylalkyl-NHC(═O)—, heterocyclylalkyl-NHC(═O)—, C₁-C₁₀alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocyclyl-OC(═O)—,carbocyclylalkyl-OC(═O)—, heterocyclylalkyl-OC(═O)—, C₁₋₁₀alkyl-NH—C(═O)—NHS(═O)₂—, carbocyclyl-NH—C(═O)—NHS(═O)₂—,heterocyclyl-NH—C(═O)—NHS(═O)₂—, C₁₋₁₀ alkyl-S(═O)₂—NH—C(═O)—,carbocyclyl-S(═O)₂—NH—C(═O)—, heterocyclyl-S(═O)₂—NH—C(═O)—, or an aminoprotecting group; wherein R¹ is optionally substituted with 1, 2 or 3substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, F,Cl, Br, I, C₁₋₄ haloalkyl, —NH₂, —NHR², —N(R²)₂, —N₃, —NO₂, —CN, —CNO,—CNS, —C(═O)OR², —C(═O)R², —OC(═O)R², —N(R²)C(═O)R², —N(R²)C(═O)OR²,—C(═O)N(R²)₂, ureido, —OR², —SR², —S(═O)—(C₁₋₆ alkyl), —S(═O)₂—(C₁₋₆alkyl), —S(═O)-aryl, —S(═O)₂-aryl, —S(═O)₂—N(R²)₂; carbocyclyloptionally substituted with 1, 2, 3, 4 or 5 R³; and heterocyclyloptionally substituted with 1, 2, 3, 4, or 5 R³;

R^(1a) is H. Alternatively, R^(1a) and R¹ together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocyclylgroup optionally substituted with 1, 2, or 3 R³;

R² is, independently, H or C₁₋₆ alkyl;

alternatively, two R² may be combined, together with the N atom to whichthey are attached, to form a 5-, 6- or 7-membered heterocyclic group;

R³ is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—,(alkyl-O)_(r)-alkyl, HO-(alkyl-O)_(r)-alkyl-, —OH, —SH, —CN, —N₃, —CNO,—CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, and H₂NS(═O)₂—;

R⁴ is, independently, selected from C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀alkynyl, —OR^(4a), —SR^(4a), —CN, halo, haloalkyl, —NH₂, —NH(alkyl),—N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —COOH, —C(═O)O-alkyl,—C(═O)alkyl, —C(O)H, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,—S(═O)₂-aryl, carbocyclyl optionally substituted with 1, 2 or 3 R⁵, andheterocyclyl optionally substituted with 1, 2 or 3 R⁵;

R^(4a) is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, carbocyclylor heterocyclyl;

R⁵ is, independently, selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—,(alkyl-O)_(r)-alkyl, HO-(alkyl-O)_(r)-alkyl-, —OH, —SH, —CN, —N₃, —CNO,—CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, and H₂NS(═O)₂—;

r is 0, 1, 2, 3 or 4;

with the proviso that when Z is —CH(OH)CH₃ and Q is

then Hy is other than

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

As used herein, the phrase “boronic acid” refers to a compoundcontaining a B(OH)₂ moiety. In some embodiments, boronic acid compoundscan form oligomeric anhydrides by dehydration of the boronic moiety. Forexample, Snyder, et al., J. Am. Chem. Soc., 1958, 80, 3611 reportoligomeric arylboronic acids. Thus, unless otherwise indicated, “boronicacid”, or a chemical formula containing a —B(OH)₂ moiety, is intended toencompass free boronic acids, oligomeric anhydrides, including but notlimited to, dimers, trimers, tetramers, and mixtures thereof.

As used herein, “boronic acid anhydride” or “boronic anhydride” refersto a compound formed by the combination of two or more molecules of aboronic acid compound of Formula (I), with loss of one or more watermolecules from the boronic acid moieties. When contacted with water, theboronic acid anhydride compound can be hydrated to release free boronicacid compound. In some embodiments, the boronic acid anhydride structurecan contain two, three, four, or more boronic acid units and can have acyclic or linear configuration. In some embodiments, the boronic acidanhydride compound exists substantially in a single oligomeric form;however, boronic acid anhydrides also encompass mixtures of differentoligomeric boronic acid anhydride as well as free boronic acids.

Non-limiting examples of boronic acid anhydrides of the inventioninclude compounds of Formula (II) and (III) where G is a moiety ofFormula (IV) and t is 0 to 10 or 1, 2, 3, or 4.

In some embodiments, at least about 80% of boronic acid present in aboronic acid anhydride compound exists in a single oligomeric anhydrideform. In further embodiments, at least about 85, about 90, about 95, orabout 99% of the boronic acid present in the boronic acid anhydrideexists in a single oligomeric anhydride form. In some embodiments, theboronic acid anhydride compound consists essentially of a singleoligomeric boronic acid anhydride. In yet further embodiments, theboronic acid anhydride compound consists of a single oligomeric boronicacid anhydride. In further embodiments, the boronic acid anhydridecompound contains a boroxine of Formula (III), wherein t is 1.

Boronic acid anhydride compounds can be prepared from the correspondingboronic acid compound by exposure to dehydrating conditions, including,for example, crystallization, lyophilization, exposure to heat, and/orexposure to a drying agent. Some suitable crystallization solventsinclude ethyl acetate, dichloromethane, hexanes, ether, benzene,acetonitrile, ethanol, and mixtures thereof.

As used herein, the phrase “boronic ester” or “boronic acid ester”refers to an ester derivative of a boronic acid compound. As usedherein, “cyclic boronic ester” is intended to mean a stable cyclicboronic moiety of general formula —B(OR)(OR) wherein the two Rsubstituents are linked together forming a cyclic moiety (e.g., 3- to10-membered cycloalkyl group) optionally further substituted with one ormore substituents or fused with (sharing at least one bond) one or morefurther carbocyclyl or heterocarbocyclyl groups. The cyclic boronicester can contain from 2 to 20 carbon atoms, and optionally, aheteroatom which can be N, S, or O. Cyclic boronic esters are well knownin the art. Examples of cyclic boronic esters include, but are notlimited to, pinanediol boronic ester, pinacol boronic ester,1,2-ethanediol boronic ester, 1,3-propanediol boronic ester,1,2-propanediol boronic ester, 2,3-butanediol boronic ester,1,1,2,2-tetramethylethanediol boronic ester, 1,2-diisopropylethanediolboronic ester, 5,6-decanediol boronic ester, 1,2-dicyclohexylethanediolboronic ester, bicyclohexyl-1,1′-diol, diethanolamine boronic ester, and1,2-diphenyl-1,2-ethanediol boronic ester.

In some embodiments, the “cyclic boronic ester” has Formula (II-a):

wherein:

D is absent, O, S, NR¹⁶, or CR^(15e)R^(15f),

R^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f) are each,independently, H, C₁-C₁₀ alkyl C₃-C₇ cycloalkyl, aryl or heteroaryl,wherein said C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl or heteroaryl areeach optionally substituted by 1, 2, 3 or 4 halo, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy, OH, amino, alkylamino, dialkylamino, aryl, orheteroaryl;

or R^(15a) and R^(15b) together with the C atoms to which they areattached form C₃-C₁₀ cycloalkyl or a 3- to 10-membered heterocycloalkylgroup, each optionally substituted by 1, 2, 3 or 4 halo, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, OH, amino, alkylamino, dialkylamino,aryl, or heteroaryl;

or R^(15c) and R^(15d) together with the C atoms to which they areattached form C₃-C₁₀ cycloalkyl or a 3- to 10-membered heterocycloalkylgroup, each optionally substituted by 1, 2, 3 or 4 halo, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, OH, amino, alkylamino, dialkylamino,aryl, or heteroaryl;

or R^(15b) and R^(15c) together with the C atoms to which they areattached and the intevening D moiety form aryl, heteroaryl, C₃-C₁₀cycloalkyl or a 3- to 10-membered heterocycloalkyl group, eachoptionally substituted by 1, 2, 3 or 4 halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ haloalkoxy, OH, amino, alkylamino, dialkylamino, aryl, orheteroaryl;

R¹⁶ is H or C₁-C₆ alkyl; and

p and q are each, independently, 1, 2 or 3.

In some embodiments, D is absent.

In some embodiments, D is NR¹⁶.

In some embodiments, D is NH.

In some embodiments, D is CH₂.

In some embodiments, R^(15a) and R^(15b) together with the C atoms towhich they are attached form C₃-C₁₀ cycloalkyl or a 3- to 10-memberedheterocycloalkyl group, each optionally substituted by 1, 2, 3 or 4halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, OH, amino,alkylamino, dialkylamino, aryl, or heteroaryl; and R^(15c) and R^(15d)together with the C atoms to which they are attached form C₃-C₁₀cycloalkyl or a 3- to 10-membered heterocycloalkyl group, eachoptionally substituted by 1, 2, 3 or 4 halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ haloalkoxy, OH, amino, alkylamino, dialkylamino, aryl, orheteroaryl.

In some embodiments, R^(15a) and R^(15b) together with the C atoms towhich they are attached form cyclopropyl, cyclobutyl, cyclopenytyl,cyclohexyl or cycloheptyl; and R^(15c) and R^(15d) together with the Catoms to which they are attached form cyclopropyl, cyclobutyl,cyclopenytyl, cyclohexyl or cycloheptyl.

In some embodiments, D is absent and R^(15b) and R^(15c) together withthe C atoms to which they are attached form aryl, heteroaryl, C₃-C₁₀cycloalkyl or a 3- to 10-membered heterocycloalkyl group, eachoptionally substituted by 1, 2, 3 or 4 halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ haloalkoxy, OH, amino, alkylamino, dialkylamino, aryl, orheteroaryl.

In some embodiments, D is absent and R^(15b) and R^(15c) together withthe C atoms to which they are attached form C₃-C₁₀ cycloalkyl optionallysubstituted by 1, 2, 3 or 4 halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy, OH, amino, alkylamino, dialkylamino, aryl, or heteroaryl.

In some embodiments, D is absent and R^(15b) and R^(15c) together withthe C atoms to which they are attached form C₃-C₁₀ cycloalkyl optionallysubstituted by 1, 2, 3 or 4 halo or C₁-C₄ alkyl.

In some embodiments, D is absent and R^(15b) and R^(15c) together withthe C atoms to which they are attached form a C₇-C₁₀ bicyclic cycloalkylgroup optionally substituted by 1, 2, 3 or 4 halo or C₁-C₄ alkyl.

In some embodiments, p and q are each 1.

In some embodiments, at least one of R^(15a), R^(15b), R^(15c), R^(15d)is other than H.

Further examples of “cyclic boronic esters”, as defined herein, include,boronic esters with the following structures:

wherein: W is a substituted or unsubstituted C₄-C₁₀ cycloalkyl ring or asubstituted or unsubstituted phenyl ring; W¹ is, independently at eachoccurrence, a substituted or unsubstituted C₃-C₆ cycloalkyl ring. GroupsR^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), p and q are,defined as provided above.

As used herein, the term “alkyl” or “alkylene” is meant to refer to asaturated hydrocarbon group which is straight-chained or branched.Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g.,n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl,t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like. Analkyl group can contain from 1 to about 20, from 2 to about 20, from 1to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, orfrom 1 to about 3 carbon atoms.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,hexadienyl, and the like.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, butynyl, pentynyl, and the like.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like. An alkyl group in which all of thehydrogen atoms are replaced with halogen atoms can be referred to as“perhaloalkyl.” Examples perhaloalkyl groups include CF₃ and C₂F₅.

As used herein, “carbocyclyl” groups are saturated (i.e., containing nodouble or triple bonds) or unsaturated (i.e., containing one or moredouble or triple bonds) cyclic hydrocarbon moieties. Carbocyclyl groupscan be mono- or polycyclic. Example carbocyclyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, norbornyl, norpinyl,norcarnyl, adamantyl, phenyl, and the like. Carbocyclyl groups can bearomatic (e.g., “aryl”) or non-aromatic (e.g., “cycloalkyl”). In someembodiments, carbocyclyl groups can have from 3 to about 20, 3 to about10, or 3 to about 7 carbon atoms.

As used herein, “aryl” refers to aromatic carbocyclyl groups includingmonocyclic or polycyclic aromatic hydrocarbons such as, for example,phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and thelike. In some embodiments, aryl groups have from 6 to about 18ring-forming carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic carbocyclyl groupsincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include bi- or poly-cyclic ring systems. Example cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also includedin the definition of cycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thecycloalkyl ring, for example, benzo derivatives of cyclopentane(indanyl), cyclohexane (tetrahydronaphthyl), and the like. Also includedin the definition of cycloalkyl are groups in which one or more of thering-forming carbon atoms is substituted by an oxo group. In someembodiments, cycloalkyl groups can have 3, 4, 5, 6, or 7 ring formingcarbon atoms. In some embodiments, cycloalkyl groups can have 0, 1, or 2double or triple ring-forming bonds.

As used herein, “heterocyclyl” groups can be saturated or unsaturatedcarbocyclyl groups wherein one or more of the ring-forming carbon atomsof the carbocyclyl group is replaced with a heteroatom such as O, S, orN. Heterocyclyl groups can be aromatic (e.g., “heteroaryl”) ornon-aromatic (e.g., “heterocycloalkyl”). Heterocyclyl groups cancorrespond to hydrogenated and partially hydrogenated heteroaryl groups.Heterocyclyl groups can contain, in addition to at least one heteroatom,from about 1 to about 20, about 2 to about 10, or about 2 to about 7carbon atoms and can be attached through a carbon atom or heteroatom.Additionally, any ring-forming carbon atom or heteroatom can besubstituted by one or two oxo or sulfide groups. Examples ofheterocyclyl groups include morpholino, thiomorpholino, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl,1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl,isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,thiazolidinyl, imidazolidinyl, and the like. In some embodiments, theheterocyclyl group is a 5- or 6-membered heterocyclyl group.

As used herein, “heteroaryl” groups are aromatic heterocarbocyclylgroups and include monocyclic and polycyclic aromatic hydrocarbons thathave at least one heteroatom ring member such as sulfur, oxygen, ornitrogen. Heteroaryl groups include, without limitation, pyridyl,N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl,quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, and thelike. In some embodiments, heteroaryl groups can have from 3 to about 20ring-forming carbon atoms, and in further embodiments from about 3 toabout 12 ring forming carbon atoms. In some embodiments, heteroarylgroups have 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In someembodiments, the heteroaryl group has at least one ring-forming N atom.

As used herein, “heterocycloalkyl” refers to a non-aromatic heterocyclylgroup including cyclized alkyl, alkenyl, and alkynyl groups where one ormore of the ring-forming carbon atoms is replaced by a heteroatom suchas an O, N, or S atom. Ring-forming carbon and heteroatoms such as S andN can further be oxidized in a heterocycloalkyl moeity. For example, thering-forming carbon or heteroatom can bear one or two oxo or sufidomoieties (e.g., >C═O, >S═O, >S(═O)₂, N→O, etc.). Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidylpyromellitic diimidyl, phthalanyl, and benzo derivatives of saturatedheterocycles such as indolene and isoindolene groups. In someembodiments, heterocycloalkyl groups have 3 to about 20 ring-formingatoms. In some embodiments, heterocycloalkyl groups have 3, 4, 5, 6, or7 ring-forming atoms. In some embodiments, heterocycloalkyl groups have0, 1, or 2 double or triple ring-forming bonds.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like. In some embodiments, alkoxy groupshave from 1 to 20, 1 to 12, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbonatoms.

As used herein, “alkoxyalkoxy” refers to an —O-alkyl-O-alkyl group.

As used herein, “thioalkoxy” refers to an alkoxy group in which the Oatom is replaced by an S atom.

As used herein, “aryloxy” refers to an —O-aryl group. An example aryloxygroup is phenoxy.

As used herein, “thioaryloxy” refers to an aryloxy group in which the Oatom is replaced by an S atom.

As used herein, “aralkyl” refers to an alkyl moiety substituted by anaryl group. Example aralkyl groups include benzyl and naphthylmethylgroups. In some embodiments, aralkyl groups have from 7 to 11 carbonatoms.

As used herein, “amino” refers to an —NH₂ group. “Alkylamino” refers toan amino group substituted by an alkyl group and “dialkylamino” refersto an amino group substituted by two alkyl groups. On the contrary,“aminoalkyl” refers to an alkyl group substituted by an amino group.

As used herein, “carbonyl” refers to >C═O.

As used herein, “carboxy” or “carboxyl” refers to —COOH.

As used herein, “hydroxy” refers to —OH.

As used herein, “mercapto” refers to —SH.

As used herein, “ureido” refers to —NHCONH₂.

As used herein, “sulfinyl” refers to >SO.

As used herein, “sulfonyl” refers to >SO₂.

As used herein, “oxy” refers to —O—.

The above chemical terms can be combined to refer to moieties containinga combination of chemical groups. This combination term is generallyread such that a recited term is understood to be a substituent of afollowing term. For example, “alkylcarbonylalkenyl” refers to an alkenylgroup substituted by a carbonyl group which in turn is substituted by analkyl group. The following terms can also exemplify such combinations.

As used herein, “carbocyclylalkyl” refers to an alkyl moiety substitutedby a carbocyclyl group. Example carbocyclylalkyl groups include“aralkyl” (alkyl substituted by aryl) and “cycloalkylalkyl” (alkylsubstituted by cycloalkyl).

As used herein, “carbocyclylalkenyl” refers to an alkenyl moietysubstituted by a carbocyclyl group. Example carbocyclylalkenyl groupsinclude “aralkenyl” (alkenyl substituted by aryl) and“cycloalkylalkenyl” (alkenyl substituted by cycloalkyl).

As used herein, “carbocyclylalkynyl” refers to an alkynyl moietysubstituted by a carbocyclyl group. Example carbocyclylalkynyl groupsinclude “aralkynyl” (alkynyl substituted by aryl) and“cycloalkylalkynyl” (alkynyl substituted by cycloalkyl).

As used herein, “heterocyclylalkyl” refers to an alkyl moietysubstituted by a heterocarbocyclyl group. Example heterocyclylalkylgroups include “heteroarylalkyl” (alkyl substituted by heteroaryl) and“heterocycloalkylalkyl” (alkyl substituted by heterocycloalkyl).

As used herein, “heterocyclylalkenyl” refers to an alkenyl moietysubstituted by a heterocyclyl group. Example heterocarbocyclylalkenylgroups include “heteroarylalkenyl” (alkenyl substituted by heteroaryl)and “heterocycloalkylalkenyl” (alkenyl substituted by heterocycloalkyl).

As used herein, “heterocyclylalkynyl” refers to an alkynyl moietysubstituted by a heterocarbocyclyl group. Example heterocyclylalkynylgroups include “heteroarylalkynyl” (alkynyl substituted by heteroaryl)and “heterocycloalkynylalkyl” (alkynyl substituted by heterocycloalkyl).

As used herein, the phrase “5- or 6-membered heterocyclic groupoptionally fused with an aryl or heteroaryl group, wherein said 5- or6-membered heterocyclic group contains at least one ring-forming N atom”refers to 5- or 6-membered heterocycloalkyl groups or 5- or 6-memberedheteroaryl groups, each containing within the 5- or 6-membered ring atleast one N atom and optionally additional heteroatoms (e.g., 1, 2 or 3additional heteroatoms selected from N, O and S). Example 6-memberedheterocyclic groups containing at least one ring-forming N atom includearomatics such as pyridyl (i.e., pryidinyl), pyrimidinyl, pyrazinyl,triazinyl, and the like. Example 6-membered heterocyclic groupscontaining at least one ring-forming N atom include non-aromatics suchas piperidinyl, piperazinyl, morpholino, and the like. Example5-membered heterocyclic groups containing at least one ring-forming Natom include aromatics such as imidazolyl, pyrrolyl, pyrrazolyl,trizaolyl, oxoazoyl, thiazolyl and the like. Example 5-memberedheterocyclic groups containing at least one ring-forming N atom includenon-aromatics such as pyrrolidine, imidazolino, imidazolidino, and thelike. The 5- or 6-membered ring can be attached through either a C atomor a heteroatom. As stated above, the 5- or 6-membered ring can be fusedto an aryl or heteroaryl group, meaning that the 5- or 6-membered ringshares a bond with an aryl or heteroaryl group. The fused aryl orheteroaryl group can be a 5- or 6-membered group such as phenyl,naphthyl, pyridyl, pyimidinyl, pyrazinyl, triazinyl, imidazolyl,pyrrolyl, pyrrazolyl, trizaolyl, oxoazoyl, thiazolyl and the like.Example 5- or 6-membered heterocyclic groups containing at least onering-forming N atom and which are fused to an aryl or heteroaryl groupinclude quinolinyl, isoquinolinyl, quinoxalinyl, indolyl, quinazolinyl,benzoimidazolyl, benzothiazolyl, benzoxazolyl and the like. The 5- or6-membered heterocyclic group containing at least one ring-forming Natom and which are fused to an aryl or heteroaryl are preferablyattached through a C or heteroatom of the 5- or 6-membered heterocyclicgroup.

As used herein, the phrase “protecting group” refers to a chemicalfunctional group that can be selectively appended to and removed fromfunctionalities, such as hydroxyl groups, amino groups, and carboxylgroups. Protecting groups are usually introduced into a chemicalcompound to render such functionality inert to chemical reactionconditions to which the compound is exposed. Any of a variety ofprotecting groups can be employed with the present invention. Aprotecting group of an amino moiety can be referred to as an “aminoprotecting group.” Amino protecting groups can have the formulasaryl-SO₂—, alkyl-SO₂—, aryl-C(═O)—, aralkyl-C(═O)—, alkyl-C(═O)—,aryl-OC(═O)—, aralkyl-OC(═O)—, alkyl-OC(═O)—, aryl-NHC(═O)—,alkyl-NHC(═O)—, and the like, wherein said alkyl, aryl and aralkylgroups may be substituted or unsubstituted. Example amino and guanidinoprotecting groups can also include t-butyloxycarbonyl (BOC),fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), and aphthalimido group. Further representative protecting groups can be foundin T. W. Green and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which isincorporated herein by reference in its entirety.

As used herein, “substituted” indicates that at least one hydrogen atomof a chemical group is replaced by a non-hydrogen moiety. Examplesubstituents include F, Cl, Br, I, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆,alkynyl, haloalkyl, NR^(E)R^(F), N₃, NO₂, CN, CNO, CNS, C(═O)OR^(E),R^(E)CO, R^(E)C(═O)O, R^(E)CONR^(E), R^(E)R^(F)NCO, ureido, OR^(E),SR^(E), SO₂-alkyl, SO₂-aryl, and SO₂—NR^(E)R^(F), wherein R^(E) andR^(F) are each, independently, H or C₁-C₆ alkyl. Alternatively, R^(E)and R^(F) may be combined, with the nitrogen to which they are attached,to form a 5 to 7 membered heterocyclic ring, for example pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, and N-methylpiperazinyl. When achemical group herein is “substituted” it may have up to the fullvalance of substitution, provided the resulting compound is a stablecompound or stable structure; for example, a methyl group may besubstituted by 1, 2, or 3 substituents, a methylene group may besubstituted by 1 or 2 substituents, a phenyl group may be substituted by1, 2, 3, 4, or 5 substituents, and the like.

As used herein, “leaving group” refers to any group that can be replacedby a nucleophile upon nucleophilic substitution. Example leaving groupsinclude, halo (F, Cl, Br, I), hydroxyl, alkoxy, mercapto, thioalkoxy,triflate, alkylsulfonyl, substituted alkylsulfonate, arylsulfonate,substituted arylsulfonate, heterocyclosulfonate or trichloroacetimidate.Representative examples include p-(2,4-dinitroanilino)benzenesulfonate,benzenesulfonate, methylsulfonate, p-methylbenzenesulfonate,p-bromobenzenesulfonate, trichloroacetimidate, acyloxy,2,2,2-trifluoroethanesulfonate, imidazolesulfonyl and2,4,6-trichlorophenyl.

As used herein “stable compound” or “stable structure” refers to acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and preferably capable offormulation into an efficacious therapeutic agent. The present inventionis directed only to stable compounds.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms.

In addition to the above, the compounds herein described may haveasymmetric centers which result in one enantiomer of a compound ofFormula (I) demonstrating superior biological activity over the oppositeenantiomer. When required, separation of the racemic material can beachieved by methods known in the art.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers. Tautomeric forms can be in equilibrium orsterically locked into one form by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like. The pharmaceuticallyacceptable salts of the present invention can be synthesized from theparent compound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and in theJournal of Pharmaceutical Science, 66, 2 (1977), the disclosures of eachof which are hereby incorporated by reference.

Synthesis

Compounds of the invention, including salts and solvates thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C)infrared spectroscopy, spectrophotometry (e.g., UV-visible), or massspectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

Compounds of the invention can be prepared according to methods forpreparing aminoboronic acids, esters thereof, and related compoundsdescribed in the art, such as in U.S. Pat. No. 4,537,773, and in U.S.Pat. No. 5,614,649, each of which is incorporated herein by reference inits entirety. In some embodiments, the present compounds can be preparedby the sequential coupling of three fragment components (F1, F2, and F3)as described below.

F1 Fragment

Synthesis of compounds of the invention can involve a boron-containingfragment (F1) having a general structure indicated by Formula (A).

The boronic ester moiety of F1 can include, for example, a diol estersuch as is indicated by the loop connecting oxygen atoms in Formula (A).

Stereochemistry at the carbon atom alpha to the boron atom in Formula(A) can be controlled using an asymmetric boronic ester group in thepreparation of F1. For example, pinanediol esters of boronic acid canfacilitate the preparation or stereochemically pure, or substantiallystereochemically pure, F1 fragment. As an example, the F1 fragment canbe prepared by reacting a compound of Formula (B) (showing a pinanediolboronic ester obtained from (+)-pinanediol) with a strong base (e.g.,lithium diisopropylamide or lithium dicyclohexylamide) in the presenceof dichloromethane or dibromomethane, followed by addition of a Lewisacid, (e.g., ZnCl₂, ZnBr₂, or FeCl₃) to yield a compound of Formula (C)(where L is halo) having a newly introduced stereocenter at the carbonalpha to the boron.

The compound of Formula (C) can, in turn, be reacted with an alkaliamide (e.g., lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide) orother nucleophile that effectively inverts the newly formed stereocenter(such as by an SN2 type mechanism) and introduces an amine group (NR₂)in place of the leaving group L (e.g., chloro), forming a compound ofFormula (D) (where each R can independently be, e.g., alkyl, Si(alkyl)₃,aryl, or aralkyl).

The compound of Formula (D) can be further reacted with an agent capableof converting the NR₂ group to NH₂, or salt thereof, to form an F1fragment substantially capable of coupling with a further fragmentthrough the amine. A suitable agent for converting the NR₂ group to NH₂can be a protic acid such as HCl such as when R is a silyl group (e.g.,trimethylsilyl).

The compound of Formula (B) can also be prepared according to a two stepprocedure involving reaction of a trialkoxyborane, such astriisopropoxyborane, with (1S,2S,3R,5S)-(+) pinanediol, to give amono-alkoxy [(1S,2S,3R,5S)-(+) pinanediol]borane intermediate whereintwo of the alkoxy groups of the trialkoxy borane are replaced by(1S,2S,3R,5S)-(+) pinanediol. This mixed pinanediol alkoxy borane, uponreaction with the appropriate organometallic derivative, e.g. theGrignard reagent R′CH₂MgBr (where R′ is prop-2-yl) or the alkyl lithiumR′CH₂Li (where R′ is prop-2-yl), gives compound (B) in good yields andpurities. The process starting from triisopropoxyborane to give theintermediate mixed pinanediol isopropoxy borane (F) and the compounds offormula (B) is depicted in the following scheme:

F2 Fragment

The mid-section of compounds of the present invention can be representedby fragment F2 which couples to fragment F1 by peptide bond formationfor form an F2-F1 intermediate. Methods for coupling compounds throughpeptide bonds, or amide bonds, are well known in the art and described,for example, in The Peptides: Analysis, Synthesis, Biology, Vol. I.,eds. Gross, et al., Academic Press, 1979, which is incorporated hereinby reference in its entirety. An example F2 fragment is provided inFormula (E) (Pg is an amino protecting group, Z is defined herein).Additionally, protection of the amino group of amino acids using Boc orother amino protecting groups is well known in the art.

Compounds of Formula (E) that are amino acids or amino acid derivativesare available commercially or prepared by routine methods. For example,aza-serines can be prepared generally by the Hoffman Rearrangement(Hoffman's Reaction) using, for example, asparagine where the amide ofthe asparagine side chain is converted to an amine (which can besubsequently protected). Methods for carrying out HoffmanRearrangements, such as for amino acids, are known in the art and alsoprovided in the Examples below. Additionally aza-serines can be preparedas disclosed in Zhang, et al. J. Org. Chem., 1997, 62, 6918-6920, whichis incorporated herein by reference in its entirety. F2 fragments can beobtained from commercial sources or made by methods known to one skilledin the art.

F3 Fragments

A further fragment (F3) can be coupled to the F2 fragment of the F2-F1intermediate by any of various means such as by nucleophilicsubstitution or addition reactions where, for example, F2 contains anucleophile (e.g., amine) and F3 contains an electrophile (e.g., CO) andoptionally a leaving group (e.g., halo, hydroxy, alkoxy, alkylsulfonyl,arylsulfonyl, and the like). Example F3 fragments can have the formulaHyCOOH. Coupling of HyCOOH to the F2-F1 intermediate can be carried outaccording to standard procedures for peptide bond formation to preparecompounds having the formula F3-F2-F1 where the F3 and F2 fragments arecoupled via an amide bond. Other coupling means are known in the art andare also suitable. F3 fragments can be obtained from commercial sourcesor made by methods known in the art.

F3-F2-F1 Product

The F3-F2-F1 product includes compounds of the invention and can also bederivatized to prepare additional compounds of the invention by routinemethods in the art. For example, compounds of the invention where Z is—CH₂NH₂ can be prepared by removal of an amino protecting group such asbenzyloxycarbonyl group (—C(═O)OCH₂(C₆H₅)) which is attached to one ofthe nitrogens of the azaserine group (e.g., compounds of Formula (I)where Z is —CH₂NHR¹ and R¹ is —C(═O)OCH₂(C₆H₅)). Removal of thebenzyloxycarbonyl group can be carried out by treatment with a reducingagent, such as a hydrogenation reagent. In some embodiments, thehydrogenation reagent contains H₂ which is optionally used in thepresence of a metal catalyst (e.g., Pd/C 10%). Hydrogenation can befurther carried out in the presence of a protic acid such as HCl and ina suitable hydrogenation solvent containing, for example, an alcohol(e.g., methanol) and/or an ether solvent (e.g., 1,4-dioxane).

Certain compounds of the invention wherein Z is —CH₂NHR¹ can be preparedby removal of an R¹ amino protecting group to form the correspondingdeprotected amine (such as described above) followed by reaction with areagent having the formula R¹X^(L), (with the exception that R¹ is notH; and X^(L) is a leaving group such as halo or a sulfonic acidderivative; or wherein R¹ and X^(L) taken together represent, forexample, a reactive alkyl, carbocyclyl or heterocarbocyclyl isocyanate,or an alkyl, carbocyclyl, heterocarbocyclyl sulphonylisocyanate).

Boronic Ester/Boronic Acid Conversion

Compounds of the invention containing boronic esters, such as pinanediolesters, can be hydrolyzed by any suitable means to prepare correspondingboronic acid (—B(OH)₂) derivatives. Hydrolysis conditions can includecontacting a boronic ester with excess acid, such as a protic acid likeHCl.

Conversely, boronic acids can be esterified by contacting the acidcompound (—B(OH)₂) with an alcohol such as a diol for sufficient time toproduce the corresponding ester. The esterification reaction can be acidor base catalyzed.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES Example A.1 Synthesis of intermediate(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt Step 1:2-(2-methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole

A mixture of (+)-pinanediol (23.9 g, 0.140 mol) and2-methylpropylboronic acid (15 g, 0.147 mol) in diethyl ether (300 ml)was stirred at room temperature for 24 h. The mixture was dried overanhydrous sodium sulfate and purified by column chromatography (Silicagel 230-400 mesh), eluting with hexane:ethyl acetate 90:10 mixture. Theproduct was obtained as a clear oil (32.6 g, 94% yield).

¹H NMR (DMSO-d₆): 4.28 (1H, dd, J=8.8 Hz, 2.0); 2.30 (1H, m); 2.18 (1H,m); 1.96 (1H, t, J=5.3); 1.86 (1H, m); 1.78 (1H, set, J=6.8); 1.68 (1H,m); 1.30 (3H, s); 1.25 (3H, s); 1.01 (1H, d); 0.9 (6H, d, J=6.6); 0.81(3H, s); 0.69 (2H, m).

Step 2:2-[(1S)-1-chloro-3-methylbutyl]-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole

A solution of lithium diisopropylamide was prepared by addition of 10.0M butyl lithium solution in hexane (25.4 ml, 0.254 mol) to a solution ofdiisopropylamine (35.7 ml, 0.254 mol) in dry tetrahydrofuran (60 ml), at−50° C., and allowing the temperature to rise to −30° C. This solutionwas transferred via canula into a solution of2-(2-methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaboroleof Step 1 (50 g, 0.212 mol) and CH₂Cl₂ (50 ml, 0.848 mol) in drytetrahydrofuran (700 ml), while keeping the temperature below −70° C. A1.0 M solution of dry zinc chloride in diethyl ether (339 ml, 0.339 mol)was then added over a 30 minutes period while keeping the internaltemperature below −70° C. The reaction mixture was stirred at −78° C.for 3 hours, then allowed to warm to room temperature. After removal ofthe solvents by rotary evaporation the residue was partitioned betweenpetroleum ether (1000 ml) and a 10% aqueous solution of ammoniumchloride (800 ml). The aqueous layer was further extracted withpetroleum ether (300 ml). The combined organic phases were dried overanhydrous sodium sulfate and concentrated. The product was obtained as abrown oil (59.0 g, 98% yield) containing about 9% mol/mol of startingmaterial (¹H-NMR), and was used in the subsequent step without furtherpurification.

¹H NMR (DMSO-d₆): 4.43 (1H, dd, J=8.8, 1.8); 3.59 (1H, m); 2.33 (1H, m);2.21 (1H, m); 2.01 (1H, m); 1.88 (1H, m); 1.84-1.55 (5H, m); 1.34 (3H,s); 1.26 (3H, s); 1.09 (1H, J=10.1); 0.9 (3H, d, J=6.8); 0.87 (3H, d,J=6.4); 0.82 (3H, s).

Step 3:N,N-Bis(trimethylsilyl)-(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine

A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran(189 ml, 0.189 mol) was added, over 30 minutes, to a solution of crude2-[(1S)-1-chloro-3-methylbutyl]-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaboroleof Step 2 (59.0 g, 91% purity, 0.189 mol) in tetrahydrofuran (580 ml)while cooling at −78° C. The reaction mixture was allowed to slowly warmto room temperature overnight. The solvent was removed by rotaryevaporation and the residue taken up with dry hexane (800 ml). Theresulting suspension was stirred at room temperature for 2 hours, thenthe solid was removed by filtration on a celite cake, which was washedwith dry hexane (3×100 ml). The filtrate was concentrated giving asatisfactorily pure product as a brown oil (79 g) in practicallyquantitative yield. The product was used for the subsequent step withoutfurther purification.

¹H NMR (DMSO-d₆): 4.33 (1H, dd, J=1.5 Hz, 8.6); 2.58 (1H, m); 2.29 (1H,m); 2.18 (1H, m); 1.95 (1H, t, J=5.9); 1.85 (1H, m); 1.9-1.55 (3H, m);1.31 (3H, s); 1.24 (3H, s); 1.17 (1H, m); 1.01 (1H, d, J=10.6); 0.85(3H, d, J=6.6), 0.83 (3H, d, J=6.6); 0.80 (3H, s); 0.08 (18H, s).

Step 4:(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt

To a solution of crudeN,N-bis(trimethylsilyl)-(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamineof Step 3 (79 g, 0.193 mol) in a mixture of dioxane (100 ml) and diethylether (200 ml), a 4 N solution of hydrogen chloride in dioxane (193 ml,0.772 mol) was added, while cooling at 0° C. The mixture was thenstirred at room temperature for 4 hours and concentrated. The residuewas taken up with anhydrous hexane (500 ml) and a 2 M solution ofhydrogen chloride in diethyl ether (48 ml, 0.096 mol) was added. Themixture was stirred at 0° C. for 1 hour, then concentrated. The residuewas taken up with anhydrous hexane and the resulting suspension wasstirred at room temperature overnight. The solid was collected byfiltration and dried under vacuum affording 38.1 g of product (66%yield). A second crop (4.13 g, 7% yield) was obtained from the motherliquors.

¹H NMR (DMSO-d₆): 7.85 (3H, br); 4.45 (1H, dd, J=9.2 Hz); 2.78 (1H, m);2.34 (1H, m); 2.21 (1H, m); 2.01 (1H, t, J=5.3); 1.89 (1H, m); 1.82-1.65(2H, m); 1.49 (1H, m); 1.38 (3H, s); 1.27 (3H, s); 1.12 (1H, d, J=1.12);0.87 (6H, d, J=6.6); 0.83 (3H, s).

Example A.2 Alternate Synthesis of Intermediate2-(2-methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaboroleStep 1:2-(1-methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole

To a solution of (1S,2S,3R,5S)-(+)-pinanediol (50.0 g, 0.293 mol) inanhydrous tetrahydrofuran (350 ml) triisopropoxy borane was slowly addedwhile stirring at 0° C. under nitrogen. After 2 h the solvent wasremoved by rotary evaporation. The oily residue was redissolved inhexane (150 ml) and the solution was filtered to remove a very smallamount of a white solid. The filtrate was concentrated by rotaryevaporation affording the product as a clear oil (62.6 g, 90% yield).

¹H NMR (DMSO-d₆): 4.31-4.20 (2H, m); 2.34-2.16 (2H, m); 1.96 (1H, t,J=5.5); 1.90-1.85 (1H, m); 1.74-1.67 (1H, m); 1.32 (3H, s); 1.31 (1H, d,J=7.6); 1.25 (3H, s); 1.14 (3H, d, J=6.1); 1.13 (3H, d, J=6.1); 0.81(3H, s).

Step 2:2-(2-methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole

A 2M solution of isobutyl magnesium bromide in diethyl ether (131.5 ml,0.263 mol) was added dropwise, in 1 hour, to a solution of2-(1-methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaboroleobtained in Step 1 (62.6 g, 0.263 mol), in anhydrous tetrahydrofuran(330 ml) while stirring at −78° C., under nitrogen. The mixture was thenallowed to warm to room temperature, then transferred in a mixture of 2Nsulfuric acid (150 ml) and diisopropyl ether (250 ml). After stirringfor 10 minutes, a saturated solution of NaCl was added (100 ml) and thelayers were separated. The organic phase was washed with brine (100 ml),dried over sodium sulfate and concentrated. The residue was purified bycolumn chromatography (silica gel) eluting with 5% diethyl ether inhexane. The product was obtained as a clear oil (38.45 g, 62% yield).

Example B.2 Preparation of Intermediate Carbamic acid 1,1-dimethylethylester,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]-

Boc-L-threonine (870 mg, 3.97 mmol, 1.2 eq.) was dissolved in DMF dry(30 ml) at r.t. To this solution, TBTU(N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate;1270 mg, 3.97 mmol, 1.2 eq.) was added and the mixture was cooled to 0°to 5° C. Then NMM (N-methylmorpholine, 0.9 ml, 8.27 mmol, 2.5 eq.) and(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt of Example A.1 (1000 mg, 3.3 mmol, 1 eq.) were added.The mixture was stirred at r.t. for 16 h, then was extracted with ethylacetate (100 ml) washed with the following solutions: citric acid 2% (50ml), sodium bicarbonate 2% (50 ml), NaCl 2% (50 ml). The organicsolution was dried over sodium sulphate anhydrous, filtered andevaporated under reduced pressure to give 1290 mg of glassy solid. Yield84.3%. M.p. 25°-30° C.

¹H NMR (DMSO-d₆): 8.88 (1H, br); 6.49 (1H, d, J=8.4 Hz); 4.88 (1H, d,J=5.8); 4.05 (1H, dd); 3.93 (1H, m); (1H, m); 2.51 (1H, m); 2.19 (1H,m); 2.01 (1H, m); 1.83 (1H, t, J=5.9), 1.78 (1H, m); 1.68 (1H, m); 1.62(1H, m); 1.39 (9H, s); 1.34 (1H, d, J=10.0); 1.24 (3H, s); 1.22 (3H, s);1.06 (3H, d, J=6.4); 0.85 (6H, d, J=6.4); 0.80 (3H, s)

Example B.3 Preparation of Intermediate Carbamic acid benzyl ester,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]

This intermediate was prepared using procedures analagous to those ofExample B2 using appropriate starting materials.

M.p. 57-60° C. ¹H NMR (DMSO-d₆): 8.66 (1H, s); 7.40-7.29 (5H, m); 7.09(1H, d, J=8.75); 5.06 (2H, s); 4.90 (1H, J=5.68); 4.11-3.99 (2H, m);3.91-3.77 (1H, m); 2.58-2.53 (1H, m); 2.26-2.14 (1H, m); 2.07-1.97 (1H,s); 1.84 (1H, t, J=5.52); 1.81-1.75 (1H, m); 1.73-1.58 (2H, m); 1.33(2H, d, J=10.1); 1.27-1.20 (7H, m); 1.06 (3H, t, J=6.27); 0.91-0.79 (9H,m).

Example B.4 Preparation of Intermediate(2S)-2-[(1,1-Dimethylethoxycarbonyl)amino]-3-[(4-methylbenzoyl)amino]propanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-

(2S)-2-[(1,1-Dimethylethoxycarbonyl)amino]-3-[(4-methylbenzoyl)amino]-propanoicacid, (650 mg, 2 mmol, 1.2 eq.) of Example G.6, was dissolved in DMF dry(15 ml), under nitrogen, and TBTU (640 mg, 2 mmol, 1.2 eq.) was added atr.t. The mixture was cooled at 0°-5° C. with ice bath and NMM (0.55 ml,5 mmol, 2.5 eq.) and(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt, (500 mg, 1.65 mmol, 1 eq.) of Example A.1, wereadded. The mixture was stirred overnight, poured in water (200 ml) andextracted with ethyl acetate (100 ml). The organic layer was washed withthe following solutions: citric acid 2% (20 mL), sodium bicarbonate 2%(20 ml), NaCl 2% (20 ml). The organic solution was dried over sodiumsulphate anhydrous, filtered and evaporated to give 740 mg of glassysolid (quantitative yield).

¹H NMR (DMSO-d₆) 8.76 (1H, br); 8.28 (1H, t, J=5.31 Hz); 7.71 (2H, d,J=7.9); 7.26 (2H, d, J=7.9); 6.97 (1H, d, J=8.0); 4.27 (1H, m); 4.07(1H, dd, J=8.2, 1.5); 3.48 (2H, m), 2.58 (1H, m); 2.35 (3H, s); 2.19(1H, m); 2.02 (1H, m); 1.83 (1H, t, J=4.9); 1.78 (1H, m); 1.62 (2H, m);1.35 (12H, m); 1.24 (3H, s); 1.23 (3H, s); 0.82 (3H, d); 0.80 (3H, d);0.78 (3H, s).

Example B.5 Preparation of Intermediate2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(hexanoylamino)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic acid,(300 mg, 1 mmol, 1.2 eq.) of Example G.7 was dissolved in DMF dry (25ml), under nitrogen, and TBTU (318 mg, 1 mmol, 1.2 eq.) was added atr.t. The mixture was cooled at 0°-5° C. with ice bath and NMM (0.27 ml,2.47 mmol, 2.47 eq.) and(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt, (250 mg, 0.82 mmol, 1 eq.) of Example A.1, wereadded. The mixture was stirred 3 h, poured in water (150 ml) andextracted with ethyl acetate (100 ml). The organic layer was washed withthe following solutions: citric acid 2% (50 mL), sodium bicarbonate 2%(50 ml), NaCl 2% (50 ml). The organic solution was dried over sodiumsulphate anhydrous, filtered and evaporated to give 450 mg of glassysolid. Yield quantitative.

Analytical data: ¹H NMR (DMSO-d₆). δ_(H), 8.71 (1H, br d, J=2.6 Hz);7.73 (1H, br t, J=5.9 Hz); 6.81 (1H, d, J=8.2); 4.10 (2H, m); 3.24 (2H,m); 2.56 (1H, m); 2.19 (1H, m); 2.03 (3H, m); 1.83 (1H, t, J=5.5); 1.78(1H, m); 1.64 (2H, m); 1.47 (2H, m); 1.36 (9H, s); 1.4-1.15 (9H, m);1.24 (3H, s); 1.21 (3H); 0.83 (9H, m); 0.79 (3H, s)

Example B.6 Preparation of Intermediate2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionicacid, (1.39 g, 3.83 mmol, 1.2 eq.) of Example G.8, was dissolved in DMFdry (20 ml), under nitrogen, and TBTU (1.23 g, 3.83 mmol, 1.2 eq.) wasadded at r.t. The mixture was cooled at 0°-5° C. with ice bath and NMM(1 ml, 9.57 mmol, 3 eq.) and(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt, (0.96 g, 3.19 mmol, 1 eq.) of Example A.1, wereadded. The mixture was stirred 2 h, poured in water (200 ml) andextracted with ethyl acetate (100 ml). The organic layer was washed withthe following solutions: citric acid 2% (50 mL), sodium bicarbonate 2%(50 ml), NaCl 2% (50 ml). The organic solution was dried over sodiumsulphate anhydrous, filtered and evaporated with diethyl ether to give1.5 g of white solid. Yield 77%.

Analytical data:

¹H NMR (DMSO-d₆).

δ_(H), 8.54 (1H, d, J=2.9 Hz); 7.91 (2H, m); 7.75 (1H, t, J=5.9); 7.50(2H, t, J=8.8); 6.83 (1H, d, J=8.4); 4.19 (1H, br d, J=8.2); 4.14 (1H,m); 3.01 (2H, m); 2.69 (1H, m); 2.25 (1H, m); 2.09 (1H, m); 1.90 (1H, t,J=5.7); 1.85 (1H, m); 1.8-1.6 (2H, m); 1.5-1.2 (5H, m); 1.43 (9H, s);1.29 (6H, s); 0.89 (6H, d, J=6.4); 0.86 (3H, s).

Example B.7 Preparation of Intermediate2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-propionicacid, (0.73 g, 1.90 mmol, 1.2 eq.) of Example G.9, was dissolved in DMFdry (20 ml), under nitrogen, and TBTU (0.61 g, 1.90 mmol, 1.2 eq.) wasadded at r.t. The mixture was cooled at 0°-5° C. with ice bath and NMM(0.52 ml, 4.7 mmol, 2.5 eq.) and(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt, (0.47 g, 1.6 mmol, 1 eq.) of Example A.1, wereadded. The mixture was stirred 2 h, poured in water (200 ml) andextracted with ethyl acetate (100 ml). The organic layer was washed withthe following solutions: citric acid 2% (50 mL), sodium bicarbonate 2%(50 ml), NaCl 2% (50 ml). The organic solution was dried over sodiumsulphate anhydrous, filtered and evaporated with diethyl ether to give0.95 g of crude that was purified by silica gel chromatography (eluentethyl acetate) to give 0.3 g of white foam. Yield 30%.

Analytical data: TLC silica gel (eluent ethyl acetate 100%, R.f.=0.50)

¹H NMR (DMSO-d₆).

δ_(H), 8.69 (1H, d, J=2.6 Hz); 7.90 (1H, t, J=5.7); 6.85 (2H, m); 6.74(1H, dd, J=1.5, 8.1); 6.85 (3H, m); 4.12 (2H, m); 3.73 (3H, s); 3.72(3H, s); 3.34 (2H, s); 3.31 (2H, m); 2.58 (1H, m); 2.20 (1H, m); 2.03(1H, m); 1.85 (1H, t, J=5.3); 1.79 (1H, m); 1.66 (2H, m); 1.38 (9H, s);1.40-1.15 (3H, m); 1.25 (3H, s); 1.23 (3H, s); 0.83 (6H, d, J=6.6); 0.81(3H, s).

Example B.8 Preparation of Intermediate2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionicacid, (0.41 g, 1.26 mmol, 1.2 eq.) of Example G.10, was dissolved in DMFdry (20 ml), under nitrogen, and TBTU (0.40 g, 1.26 mmol, 1.2 eq.) wasadded at r.t. The mixture was cooled at 0°-5° C. with ice bath and NMM(0.346 ml, 3.15 mmol, 2.5 eq.) and(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt, (0.31 g, 1 mmol, 1 eq.) of Example A.1, were added.The mixture was stirred 2 h, poured in water (200 ml) and extracted withethyl acetate (100 ml). The organic layer was washed with the followingsolutions: citric acid 2% (50 mL), sodium bicarbonate 2% (50 ml), NaCl2% (50 ml). The organic solution was dried over sodium sulphateanhydrous, filtered and evaporated with diethyl ether (50 ml) to give0.58 g of white solid.

Yield 96.6%.

Analytical data: TLC silica gel (eluent ethyl acetate 100%, R.f.=0.47),m.p. 128°-130° C.

¹H NMR (DMSO-d₆).

δ_(H), 8.79 (1H, d, J=2.7 Hz); 8.69 (1H, s); 7.38 (2H, d, J=7.9); 7.22(2H, t, J=8.1); 7.00 (1H, d, J=8.1); 6.90 (1H, t, J=7.3); 6.16 (1H, t,J=5.7); 4.12 (2H, m); 3.45 (1H, m); 3.17 (1H, m); 2.60 (1H, m); 2.21(1H, m); 2.04 (1H, m); 1.85 (1H, t, J=5.3); 1.79 (1H, m); 1.66 (2H, m);1.38 (9H, s); 1.40-1.15 (3H, m); 1.26 (3H, s); 1.23 (3H, s); 0.84 (6H,d, J=6.6); 0.81 (3H, s).

Example B.9 Synthesis of Further Intermediates

Following the procedures of Examples B.4-B.8, the following compoundscan be prepared by reaction of(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt of Example A.1 and intermediates of Examples G.11,G.12 and G.13.

B.9.12-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(acetamido-)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl].

B.9.22-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(9-fluorenylmethyloxycarbamoyl)ethyl]-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl].

B.9.32-S-[(1,1-dimethylethoxycarbonyl)amino]-2-[(pentylureido)ethyl]-N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-

B.9.42-S-[(1,1-dimethylethoxycarbonyl)amino]-2-(methanesolfonamido)ethyl]-N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-

B.9.52-S-[(1,1-dimethylethoxycarbonyl)amino]-2-[(ethoxycarbonylsuccinyl]-amide)ethyl]-N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-

B.9.62-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(benzyloxycarbamoyl)ethyl]-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl].

B.9.72-S-[(1,1-dimethylethoxycarbonyl)amino]-3-[2-(1H-pyrazol)ethyl]-N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]

Example C.3 Preparation of Intermediate(2S,3R)-2-Amino-3-hydroxybutanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,hydrochloride salt

A 4 N solution of hydrogen chloride in dioxane was added to a solutionof carbamic acid 1,1-dimethylethyl ester,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]-of Example B.2, in a mixture of dioxane and diethyl ether, while coolingto 0° C. The reaction mixture was allowed to warm to room temperatureand stirred for several additional hours. The solvent was removed byrotary evaporation, the residue was treated with diethyl ether and themixture was stirred at r.t. for several days. The resulting solid wascollected by filtration affording pure product in good yield.

¹H NMR (DMSO-d₆) δ_(H), 8.62 (1H, d, J=5.0 Hz); 8.17 (3H, d, J=3.5);4.28 (1H, dd, J=8.8, 1.8); 3.78 (1H, m); 3.52 (1H, m); 3.00 (1H, m);2.28 (1H, m); 2.10 (1H, m); 1.92 (1H, t, J=5.7); 1.84 (1H, m); 1.75-1.62(2H, m); 1.43 (1H, m); 1.31 (3H, s); 1.25 (3H, s); 1.22 (1H, d, J=10.6);1.14 (3H, d, J=6.2); 0.88 (3H, d, J=6.4); 0.86 (3H, d, J=6.4); 0.81 (3H,s)

Example C.4 Preparation of Intermediate(2S)-2-Amino-3-[(4-methylbenzoyl)amino]propanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,hydrochloride salt

(2S)-2-[(1,1-Dimethylethoxycarbonyl)amino]-3-[(4-methylbenzoyl)-amino]-propanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,Example B.4, (740 mg, 1.65 mmol, 1 eq.), was dissolved in 1,4-dioxane(20 ml). To this solution, HCl 4N in 1,4-dioxane (5 ml, 19.8 mmol, 12eq.) was added and the solution stirred overnight at r.t. The solventwas removed under reduced pressure to give 800 mg of a glassy solid(quantitative yield).

¹H NMR (DMSO-d₆) 8.63 (1H, d, J=5.5 Hz); 8.38 (1H, t, J=8.4 Hz); 8.34(3H, br); 7.80 (2H, t, J=8.2); 7.28 (2H, d, J=8.2 Hz); 4.15 (1H, dd,J=8.8, 1.8); 4.02 (1H, br); 3.66 (1H, m); 3.55 (1H, m); 2.99 (1H, m);2.35 (3H, s); 2.19 (1H, m); 2.06 (1H, m); 1.86 (1H, t, J=5.7); 1.80 (1H,m); 1.64 (2H, m); 1.41 (1H, m); 1.33-1.19 (2H, m); 1.27 (3H, s), 1.21(3H, s); 1.16 (1H, d, J=10.6); 0.82 (3H, d); 0.80 (3H, d); 0.78 (3H, s).

Example C.5 2-S-amino-3-(hexanoylamino)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],hydrochloride salt

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],of Example B.5, (450 mg, 0.8 mmol, 1 eq.), was dissolved in 1,4-dioxane(15 ml). To this solution, HCl 4N in 1,4-dioxane (2.45 ml, 0.98 mmol, 12eq.) was added and the solution stirred overnight at r.t. The solventwas removed under reduced pressure to give 400 mg of a glassy solid.Yield quantitative.

Analytical data: ¹H NMR (DMSO-d₆).

δ_(H), 8.54 (1H, d, J=5.3 Hz); 8.18 (3H, br); 7.74 (1H, t, J=5.7); 4.29(1H, dd, J=1.8, 8.8); 3.83 (1H, m); 3.40 (2H, m); 3.00 (1H, m); 2.29(1H, m); 2.11 (1H, m); 2.08 (2H, t, J=7.5); 1.93 (1H, t, J=5.5); 1.84(1H, m); 1.75-1.15 (11H, m); 1.32 (3H, s); 1.24 (3H, s); 0.86 (3H, d,J=6.6); 0.84 (3H, d, J=6.6); 0.81 (3H, s).

Example C.6 Preparation of Intermediate2-S-amino-3-(4-fluorosulfonylamino)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],hydrochloride salt

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],of Example B.6, (0.7 g, 1.14 mmol, 1 eq.), was dissolved in 1,4-dioxane(20 ml). To this solution, HCl 4N in 1,4-dioxane (3.4 ml, 13.68 mmol, 12eq.) was added and the solution stirred overnight at r.t. The solventwas removed under reduced pressure to give 440 mg of a white solid.Yield 71%. Analytical data: ¹H NMR (DMSO-d₆).

δ_(H), 8.54 (1H, d, J=5.5 Hz); 8.26 (3H, br); 7.89 (3H, m); 7.48 (3H, t,J=8.8); 4.26 (1H, dd, J=1.3, 8.6); 3.84 (1H, m); 3.06 (2H, m); 2.97 (1H,m); 2.25 (1H, m); 2.03 (1H, m); 1.83 (2H, m); 1.64 (2H, m); 1.42 (1H,m); 1.35-1.15 (3H, m); 1.28 (3H, s); 1.22 (3H, s); 1.11 (1H, d, J=10.8);0.85 (6H, m); 0.80 (3H, s).

Example C.7 2-S-amino-3-(3,4-dimethoxyphenylacetamido)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],hydrochloride salt

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],of Example B.7, (0.3 g, 0.47 mmol, 1 eq.), was dissolved in 1,4-dioxane(20 ml). To this solution, HCl 4N in 1,4-dioxane (1.43 ml, 5.71 mmol, 12eq.) was added and the solution stirred overnight at r.t. The solventwas removed under reduced pressure, diethyl ether was added andevaporated to give 230 mg of a white solid. Yield 85%.

Analytical data:

¹H NMR (DMSO-d₆).

δ_(H), 8.57 (1H, br); 8.12 (3H, br); 7.91 (1H, t, J=5.7 Hz); 6.86 (2H,m); 6.76 (1H, dd, J=1.8, 8.2); 4.26 (1H, br d, J=7.3); 3.82 (1H, m);3.72 (3H, s); 3.71 (3H, s); 3.36 (2H, s); 3.34 (2H, m); 2.99 (1H, m);2.26 (1H, m); 2.10 (1H, m); 1.92 (1H, t, J=5.3); 1.83 (1H, m); 1.67 (2H,m); 1.45-1.15 (3H, m); 1.31 (3H, s); 1.23 (3H, s); 0.86 (3H, d, J=6.6);0.84 (3H, d, J=6.6); 0.80 (3H, s).

Example C.8 Preparation of Intermediate2-S-amino-3-(3-phenyl-ureido)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],hydrochloride salt

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],of Example B.8, (0.58 g, 0.1 mmol, 1 eq.), was dissolved in 1,4-dioxane(25 ml). To this solution, HCl 4N in 1,4-dioxane (3 ml, 12.1 mmol, 12eq.) was added and the solution stirred overnight at r.t. The solventwas removed under reduced pressure, diethyl ether was added andevaporated to give 0.52 g of desired product. Yield 100%.

Analytical data:

¹H NMR (DMSO-d₆).

δ_(H), 8.82 (1H, s); 8.59 (1H, d, J=5.7 Hz); 8.18 (3H, br); 7.40 (2H, d,J=7.9); 7.22 (2H, t, J=8.1); 6.90 (1H, t, J=7.3); 6.31 (1H, t, J=5.7);4.26 (1H, dd, J=1.5, 8.6); 3.89 (1H, m); 3.48 (1H, m); 3.36 (1H, m);3.01 (1H, m); 2.24 (1H, m); 2.10 (1H, m); 1.92 (1H, t, J=5.3); 1.82 (1H,m); 1.67 (2H, m); 1.50-1.15 (3H, m); 1.31 (3H, s); 1.21 (3H, s); 0.85(3H, d, J=6.6); 0.84 (3H, d, J=6.6); 0.79 (3H, s).

Example C.9 Synthesis of Further Intermediates

Following the procedures of Examples C.4-C.8, the following compoundscan be prepared starting from intermediates of Example B.9.

C.9.12-S-amino-3-(acetamido)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],HCl salt.

C.9.22-S-amino-3-(9-fluorenylmethyloxycarbamoyl)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],HClsalt.

C.9.3 2-S-amino-3-(pentylureido)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],HCl salt.

C.9.42-S-amino-3-(methanesolfonamido)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],HCl salt.

C.9.5 2-S-amino-3-[(ethoxycarbonylsuccinyl]-amide)ethyl]-)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],HClsalt.

C.9.62-S-amino-3-(benzyloxycarbamoyl)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],HCl salt.

C.9.73-[2-(1H-pyrazol)ethyl]-N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]HCl salt.

Example G.5 Preparation of Intermediate3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]-propionic acid, benzylester

Step 1: N-tert-butoxycarbonyl-L-asparagine [Commercially available]

L-asparagine (15 g, 0.113 mol, 1 eq.) and sodium carbonate (12 g, 0.113mol) were dissolved in water (225 ml) and 1,4-dioxane (225 ml) at r.t.To this solution, di-tert-butyl-dicarbonate (30 g, 0.137 mol, 1.2 eq.)was added and the mixture was stirred overnight. The solvent wasevaporated under reduced pressure until 1,4-dioxane was distilled andthe pH adjusted to 2 with HCl 37% to give a white solid that wasfiltered, washed with water and dried. Yield 91%. 24 g.

Analytical data: m.p. 175° C.-180° C. (lit. 175° C.).

¹H NMR (DMSO-d₆) 12.5 (1H, br); 7.31 (1H, br); 6.91 (1H, br); 6.87 (1H,d, J=8.4 Hz); 4.23 (1H, q, J=7.7 Hz); 2.56-2.36 (2H, m); 1.38 (9H, s).

Step 2: N-[(1,1-dimethylethoxycarbonyl)amino]-L-asparagine, benzyl ester

The compound was prepared according to Bioorg. Med. Chem., 6(1998)1185-1208. N-[(1,1-dimethylethoxycarbonyl)amino]-L-asparagine(20.7 g, 89.1 mmol, 1 eq.), of Step 1, was dissolved in methanol (500ml) and cesium carbonate (15.97 g, 49 mmol, 0.55 eq.) was added. Thesolvent was evaporated to give a white solid that was dissolved inN,N-dimethylformamide (200 ml). To the suspension, benzyl bromide (11.6ml, 98 mmol, 1.1 eq.) was added dropwise and the mixture was stirredovernight. The solvent was reduced under reduced pressure, water (300ml) was added and the mixture extracted with ethyl acetate (200 ml),washed with brine (50 ml) and the solvent removed under reduced pressureto give a crude that was suspended in n-hexane (160 ml), filtered anddried under vacuum to give 14.68 g of white solid. Yield 51%.

Analytical data: m.p. 113°-115° C.

¹H NMR (DMSO-d₆) 7.35 (6H, m); 7.13 (1H, d, J=7.9 Hz); 6.94 (1H, br s);5.10 (2H, s); 4.39 (1H, q, J=7.4 Hz); 2.6-2.4 (2H, m); 2.03 (2H, t,J=7.3); 1.37 (9H, s).

Step 3: 3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]-propionic acid,benzyl ester

N-[(1,1-dimethylethoxycarbonyl)amino]-L-asparagine, benzyl ester, (2 g,6.3 mmol, 1 eq.), of Step 2, was dissolved in acetonitrile (80 ml) andwater (80 ml). The solution was cooled to 0°-5° C. and iodobenzenediacetate (3 g, 9.3 mmol, 1.5 eq.) was added portionwise. The mixturewas stirred at 0° C. for 30′, then at r.t. for 4 h. The organic solventwas removed under vacuum, diethyl ether and HCl 1N were added. Theacqueous layer was separated and extracted with dichloromethane (100 ml)and sodium bicarbonate (3.5 g). The organic solvent was dried oversodium sulphate anhydrous, evaporated under reduced pressure to give0.65 g of colourless oil. Yield 36%

Analytical data:

¹H NMR (DMSO-d₆) 7.45-7.20 (7H, m); 7.20 (1H, d, J=7.7 Hz); 5.13 (2H, ABq, J=12.8); 4.01 (1H, m); 2.80 (2H, m); 1.38 (9H, s).

Example G.6 Preparation of Intermediate(2S)-2-[(1,1-dimethylethoxycarbonyl)amino]-3-[(4-methylbenzoyl)amino]propanoicacid

Step 1:2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-methylbenzoylamino)propionicacid, benzyl ester

3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]-propionic acid, benzylester, (690 mg, 2.34 mmol, 1 eq.), of Example G.5, was dissolved in DMFdry (20 ml) and TBTU (900 mg, 2.98 mmol, 1.2 eq.) was added. The mixturewas stirred at r.t. for 10′, cooled to 0°-5° C. with ice bath and NMM(0.51 ml, 4.68 mmol, 2 eq.) and 4-methyl benzoic acid (380 mg, 2.81mmol, 1.2 eq.) were added. The mixture was stirred at r.t. for 3 h,poured in water (100 ml) and extracted with ethyl acetate (100 ml). Theorganic layer was washed with a solution of citric acid 2% (50 ml),sodium bicarbonate 2% (50 ml), NaCl 2% (50 ml), dried over sodiumsulphate anhydrous and evaporated at reduced pressure to give 1 g ofoil. Yield quantitative.

Analytical data:

¹H NMR (DMSO-d₆) 8.46 (1H, br t, J=5.7 Hz); 7.70 (2H, d, J=8.0);7.35-7.2 (8H, m); 5.07 (2H, s); 4.29 (1H, m); 3.67 (1H, m); 3.58 (1H,m); 2.36 (3H, s); 1.37 (9H, s).

Step 2:(2S)-2-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-methylbenzoylamino)propionicacid

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-methylbenzoylamino)-propionicacid, benzyl ester, (930 mg, 2.25 mmol), of Step 1, was dissolved inmethanol (25 ml) and Pd/C 10% (90 mg) was added. The mixture washydrogenated at atmospheric pressure for 1 h. Pd/C was filtered and thesolution was evaporated under reduced pressure to give 650 mg of whitefoam. Yield 86%. Analytical data:

¹H NMR (DMSO-d₆): 12.5 (1H, br); 8.40 (1H, t, J=5.7 Hz); 7.71 (2H, d,J=8.05 Hz), 7.27 (2H, d, J=8.05 Hz); 7.09 (1H, d, J=7.9), 4.17 (1H, m);3.57 (2H, m); 2.35 (3H, s); 1.37 (9H, m).

Example G.7 Preparation of Intermediate2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic acid

Step 1:2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic acid,benzyl ester

Hexanoic acid (450 mg, 3.87 mmol, 1.2 eq.) was dissolved in DMF dry (15ml) and TBTU (1.24 g, 3.87 mmol, 1.2 eq.) was added, the mixture wasstirred at r.t. for 20′, then was cooled to 0°-5° C. with ice bath.3-amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]propionic acid, benzylester, (950 mg, 3.22 mmol, 1 eq.), of Example G.5, and NMM (1.06 ml,9.61 mmol, 2.5 eq.) were added. The mixture was stirred at r.t.overnight, poured in water (150 ml) and extracted with ethyl acetate(100 ml). The organic layer was washed with a solution of citric acid 2%(50 ml), sodium bicarbonate 2% (50 ml), NaCl 2% (50 ml), dried oversodium sulphate anhydrous and evaporated at reduced pressure to give acrude that was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate 2/1, R.f=0.52) 0.5 g of colourless oil. Yield40%.

Analytical data:

¹H NMR (DMSO-d₆).

δ_(H), 7.87 (1H, br t, J=6.2 Hz); 7.35 (5H, m); 7.14 (1H, d, J=8.2);5.07 (2H, s); 4.14 (1H, m); 3.37 (2H, m); 2.00 (2H, t, J=7.1); 1.43 (2H,m); 1.36 (9H, s); 1.3-1.1 (4H, m); 0.83 (3H, t, J=7.1 Hz)

Step 2:2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic acid

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic acid,benzyl ester (500 mg, 1.27 mmol), of Step 1, was dissolved in methanol(15 ml) and Pd/C 10% (50 mg) was added. The mixture was hydrogenated atatmospheric pressure for 1 h. Pd/C was filtered and the solution wasevaporated under reduced pressure to give 300 mg of white solid. Yield78%.

Analytical data: m.p. 123°-125° C.

¹H NMR (DMSO-d₆).

δ_(H), 12.6 (1H, br); 7.84 (1H, br t); 6.87 (1H, d, J=7.5 Hz); 4.00 (1H,m); 3.32 (2H, m); 2.04 (2H, t, J=7.5); 1.47 (2H, m); 1.38 (9H, s);1.3-1.1 (4H, m); 0.85 (3H, t, J=7.1 Hz)

Example G.8 Preparation of Intermediate2-S-tert-butoxycarbonylamino-3-(4-fluorosulfonylamino)propionic acid

Step 1:2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionicacid, benzyl ester

3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]propionic acid, benzylester (1.25 g, 4.24 mmol, 1 eq.), of Example G.5, was dissolved indichloromethane dry (20 ml) and the solution was cooled to 0°-5° C.,under nitrogen. TEA (0.65 ml, 4.67 mmol., 1.1 eq.) and4-fluoro-sulfonylchloride (0.9 g, 4.67 mmol., 1.1 eq.) indichloromethane dry (10 ml) were added. The mixture was stirred at r.t.for 1 h, evaporated under reduced pressure and diethyl ether (25 ml) wasadded and a white solid was obtained that was filtered and dried undervacuum to give 1.89 g of product. Yield 99%.

Analytical data: m.p. 105°-107° C. TLC silica gel (eluent:n-hexane/ethyl acetate 1/1, Rf=0.55).

¹H NMR (DMSO-d₆).

δ_(H), 7.91 (1H, t, J=6.2 Hz); 7.85 (2H, dd, J=5.3, 8.8); 7.43 (2H, t,J=8.8); 7.35 (5H, m); 7.15 (1H, d, J=8.2); 5.09 (2H, s); 4.14 (1H, m);3.10 (2H, m); 1.36 (9H, s).

Step 2:2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionicacid

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionicacid, benzyl ester (1.8 g, 3.98 mmol.), of Step 1, was dissolved inmethanol (30 ml) and Pd/C 10% (180 mg) was added. The mixture washydrogenated at atmospheric pressure for 1 h. Pd/C was filtered and thesolution was evaporated under reduced pressure to give 1.39 g ofcolourless oil. Yield 97%.

Analytical data:

¹H NMR (DMSO-d₆).

δ_(H), 12.7 (1H, br); 7.83 (2H, dd, J=5.3, 8.8); 7.78 (1H, br t, J=5.5);7.42 (2H, t, J=8.8); 6.87 (1H, d, J=8.6); 3.99 (1H, m); 3.03 (2H, m);1.36 (9H, s).

Example G.9 Preparation of Intermediate2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-propionicacid

Step 1:2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-propionicacid, benzyl ester

3,4-Dimethoxy-phenylacetic acid (720 mg, 3.66 mmol, 1.2 eq.) wasdissolved in DMF dry (20 ml) and TBTU (1.17 g, 3.66 mmol, 1.2 eq.) wasadded, the mixture was stirred at r.t. for 20′, then was cooled to 0°-5°C. with ice bath. 3-amino-2-S-tert-butoxycarbonylamino-propionic acid,benzyl ester (0.9 g, 3.05 mmol, 1 eq.), of Example G.5, and NMM (1.0 ml,9.15 mmol, 2.5 eq.) were added. The mixture was stirred at 0° C. for 2h, then poured in water (200 ml) and extracted with ethyl acetate (100ml). The organic layer was washed with the following solutions: citricacid 2% (20 ml), sodium bicarbonate 2% (20 ml), NaCl 2% (20 ml), driedover sodium sulphate anhydrous and evaporated at reduced pressure togive a crude that was purified by silica gel chromatography (eluent:n-hexane/ethyl acetate 1/1, R.f=0.57) to give 1 g of colourless oil.Yield 69%.

Analytical data: ¹H NMR (DMSO-d₆). δ_(H), 8.02 (1H, t, J=5.7 Hz); 7.34(5H, m); 7.17 (1H, d, J=7.7); 6.82 (2H, m); 6.71 (1H, dd, J=1.5, 8.2);5.03 (2H, s); 4.14 (1H, m); 3.71 (3H, s); 3.69 (3H, s); 3.39 (2H, m);1.36 (9H, s).

Step 2:2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-propionicacid

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-propionicacid, benzyl ester (1 g, 2.1 mmol.), of Step 1, was dissolved inmethanol (30 ml) and Pd/C 10% (10 mg) was added. The mixture washydrogenated at atmospheric pressure for 1 h. Pd/C was filtered and thesolution was evaporated under reduced pressure to give 0.73 g of whitefoam. Yield 91%.

Analytical data: ¹H NMR (DMSO-d₆). δ_(H), 12.7 (1H, br); 8.06 (1H, t,J=5.9 Hz); 7.00 (1H, d, J=8.05); 6.91 (2H, m); 6.80 (1H, dd, J=1.5,8.4); 4.08 (1H, m); 3.80 (3H, s); 3.78 (3H, s); 3.5-3.3 (2H, m); 1.36(9H, s).

Example G.10 Preparation of Intermediate2-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionic acid

Step 1:2-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionic acid,benzyl ester

3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]propionic acid, benzylester (1.14 g, 3.87 mmol, 1 eq.), of Example G.5, was dissolved indichloromethane (20 ml) at r.t. The solution was cooled to 0°-5° C. andphenyl isocyanate (0.42 ml, 3.87 mmol, 1 eq.) in dichlorometane (5 ml)was added dropwise. The solution was stirred at r.t. for 1 h, evaporatedunder reduced pressure and purified by silica gel chromatography (eluentn-hexane/ethyl acetate 1/1) to give 0.71 g of glassy solid that wassuspended in diethyl ether to give a white solid. Yield 44%. Analyticaldata: TLC silica gel (eluent n-hexane/ethyl acetate 1/1 R.f.=0.44), m.p.48°-50° C.

¹H NMR (DMSO-d₆). δ_(H), 8.68 (1H, s); 7.4-7.27 (8H, m); 7.22 (2H, t,J=8.2 Hz); 6.90 (1H, t, J=7.3); 6.26 (1H, t, J=5.7); 5.11 (2H, s); 4.12(1H, m); 3.58 (1H, m); 3.28 (1H, m); 1.38 (9H, s).

Step 2:2-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionic acid

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionicacid, benzyl ester (0.7 g, 1.7 mmol.), of Step 1, was dissolved inmethanol (25 ml) and Pd/C 10% (70 mg) was added. The mixture washydrogenated at atmospheric pressure for 1 h. Pd/C was filtered and thesolution was evaporated under reduced pressure to give 0.47 g of desiredproduct.

Yield 87%.

Analytical data: ¹H NMR (DMSO-d₆). δ_(H), 12.6 (1H, br); 8.66 (1H, s);7.37 (2H, d, J=8.1 Hz); 7.21 (2H, t, J=7.50); 7.08 (1H, d, J=7.9); 6.89(1H, t, J=7.3); 6.21 (1H, t, J=5.9); 3.98 (1H, m); 3.54 (1H, m); 3.22(1H, m); 1.38 (9H, s).

Example G.11 Synthesis of Further Intermediates

The following compounds can be prepared starting from3-amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]propionic acid, benzylester of Example G.5, with the methods described in Step 1 and Step 2 ofExamples G.6-G.10.

G.11.1 2-[(1,1-dimethylethoxycarbonyl)amino]-3-(acetamido)propionicacid.

G.11.22-[(1,1-dimethylethoxycarbonyl)amino]-3-(9-fluorenylmethyloxycarbamoyl))propionicacid.

G.11.3 2-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-pentylureido)propionicacid.

G.11.42-[(1,1-dimethylethoxycarbonyl)amino]-3-(methanesolfonamido)propionicacid.

G.11.52-[(1,1-dimethylethoxycarbonyl)amino]-3-[(ethoxycarbonylsuccinyl]-amide)ethyl]-propionicacid.

Example G.12 Preparation of Intermediate2-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3-benzyloxycarbonylamino)propionicacid

Step 1: N²-(tert-Butoxycarbonyl)-L-2,3-diaminopropionic acid

N-tert-butoxycarbonyl-L-asparagine, from step 1 of Example G.5 orcommercially available, (8 g, 0.034 mol, 1 eq.) was suspended in ethylacetate (72 ml), acetonitrile (72 ml) and water (36 ml), andiodobenzenediacetate (13.3 g, 0.041 mol, 1.2 eq.) was added at 5° C.

The mixture was stirred at 10°-25° C. for 3-4 h, then a white solid cameoff. The solid was filtered, washed with diethyl ether and dried undervacuum to give a white powder. Yield 57%. 4 g.

Analytical data: m.p. 210° C.-211° C. Silica gel(dichloromethane/methanol/acetic acid 5/3/1) Rf 0.5. ¹H NMR (DMSO-d₆)4.15 (1H, t); 3.15 (2H, m); 1.45 (9H, s);

Step 2:2-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-benzyloxycarbonylamino)propionicacid

N²-(tert-Butoxycarbonyl)-L-2,3-diaminopropionic acid, from step 1, (3.8g, 0.018 mol, 1 eq.) was dissolved in aqueous sodium carbonate 10% (2.2eq.) at 25° C. and 1,4-dioxane (38 ml). To this solution,benzylchloroformate (3 ml, 0.020 mol, 1.1 eq.) was added dropwise andthe solution was stirred at 25° C. for 3 h. At the end of the reaction,the mixture was poured in water (100 ml) and washed with diethyl ether(100 ml). To the aqueous solution, HCl 37% (6 ml) was added till pH 2and the obtained mixture was extracted with Ethyl Acetate (100 ml). Theorganic layer was separated, washed with brine and dried over sodiumsulfate anhydrous. The solvent was removed under reduced pressure togive a colourless oil that under vacuum gave a white foam. Yield 93%,5.9 g.

Analytical data: silica gel (dichloromethane/methanol/acetic acid 5/3/1)Rf 1.

¹H NMR (DMSO-d₆) 12.6 (1H br s); 7.35 (5H m); 6.94 (1H, d); 5 (2H, s);4.1 (2H, m); 1.4 (9H, s).

Example G.13 Preparation of Intermediate2-(tert-Butoxycarbonilamino)-3-pyrazol-1-yl-propionic acid

The intermediate was prepared according to the procedure described inVederas, J. Am. Chem. Soc., 1985, 107, 7105-7109.

Example H.1 Preparation of 6-Phenyl-pyrazine-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]

6-Phenyl-pyrazine-2-carboxylic acid (192 mg, 0.96 mmol) and TBTU (310mg, 0.96 mmol) were dissolved in dry DMF (4 ml), under a nitrogenatmosphere. The reaction mixture was cooled to 0° C. andN-methyl-morpholine (2.29 ml, 2.61 mmol) was added. The mixture wasstirred for 30 minutes, then (2S,3R)-2-amino-3-hydroxybutanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,hydrochloride salt of Example C.3 (350 mg, 0.87 mmol) was added and themixture was allowed to warm to room temperature. After 3 h the reactionmixture was diluted with ethyl acetate (100 ml) then washed with water(50 ml), 2% citric acid (50 ml), 2% NaHCO₃ (50 ml) and brine (50 ml).The organic phase was dried over anhydrous sodium sulfate, filtered andevaporated under reduced pressure. The residue was purified by elutionon a SPE-SI normal phase cartridge (20 g SiO₂) using first a 1:1hexane:ethyl acetate mixture, then ethyl acetate. The title compound wasobtained as a white foam (333 mg, 70 yield).

¹H NMR (DMSO-d₆): δ 9.39 (1H, s); 9.25 (1H, s); 8.96-8.92 (1H, bs); 8.52(1H, d, J=8.5); 8.29-8.21 (2H, m); 7.64-7.55 (3H, m); 5.27 (1H, d,J=5.0); 5.54-5.49 (1H, m); 4.19-4.10 (2H, m); 2.66-2.59 (1H, m);2.25-2.15 (1H, m); 2.07-2.00 (1H, m); 1.80-1.60 (3H, m); 1.35-1.26 (3H,m); 1.25 (3H, s); 1.22 (3H, s); 1.11 (3H, d, J=6.1); 0.87-0.79 (9H, m).

Example H.2 Preparation of Further Compounds of the Invention

Further compounds of the invention are listed below which can be madeaccording to procedures analogous to those described for Example H.1using the appropriate carboxylic acid such as described in Example M.1.Those compounds listed below which are characterized by NMR data wereactually prepared.

Ex # Structure Chemical Name and Analytical Data H.2.1

Pyridine-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]H.2.2

Pyridine-3-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]H.2.3

Quinoline-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1HNMR (DMSO-d6): 9.00-8.95 (1 H, bs); 8.76 (1 H,d, J = 8.4); 8.61 (1 H, d,J = 8.4); 8.22-8.10 (3 H, m);7.90 (1 H, t, J = 7.6); 7.75 (1 H, t, J =7.5); 5.28 (1 H, d,J = 4.8); 4.53-5.48 (1 H, m); 4.18-4.10 (2 H, m);2.67-2.60 (1 H, m); 2.26-2.18 (1 H, m); 2.08-2.00 (1 H, m);1.86-1.78 (2H, m); 1.74-1.60 (2 H, m); 1.36-1.26 (2 H,m); 1.24 (3 H, s); 1.21 (3 H,s); 1.14 (3 H, d, J = 5.9);0.86-0.79 (9 H, m) H.2.4

Quinoxaline-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1H-NMR(DMSO-d6): 9.57 (1 H, s); 8.97 (1 H, br. s),8.67 (1 H, d, J = 8.6);8.35-8.26 (2 H, m); 8.11-8.05 (2 H,m); 5.34 (1 H, d, J = 5.0); 4.58 (1H, dd, J = 8.4, 4.4);4.23-4.16 (2 H, m); 2.75-2.68 (1 H, m); 2.31-2.22(1 H,m); 2.12-2.04 (1 H, m); 1.90 (1 H, t, J = 5.5); 1.87-1.81(1 H, m);1.77-1.65 (2 H, m); 1.44-1.24 (3 H, m); 1.30(3 H, s); 1.27 (3 H, s);1.21 (3 H, d, J = 6.3);0.89 (6 H, d, J = 6.5); 0.86 (3 H, s). H.2.5

5-Phenyl-pyrazine-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1HNMR (DMSO-d6): 9.52 (1 H, s); 9.18 (1 H, s); 8.91(1 H, s); 8.66 (1 H, d,J = 8.5); 8.29-8.24 (2 H, m); 7.65-7.57 (3 H, m); 5.27 (1 H, d, J =4.7); 4.51-4.45 (1 H, m);4.16-4.09 (2 H, m); 2.66-2.59 (1 H, m);2.25-2.15 (1 H,m); 2.07-1.99 (1 H, m); 1.80-1.70 (2 H, m); 1.65-1.60(2H, m); 1.40-1.30 (3 H, m); 1.25 (3 H, s); 1.22 (3 H,s); 1.13 (3 H, d, J= 6.1); 0.87-0.79 (9 H, m) H.2.6

5-Phenyl-pyridine-3-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]M.p.135-140° C.1H-NMR (DMSO-d6): 9.06 (1 H, s); 9.02 (1 H, s);9.00 (1 H, br.s); 8.66 (1 H, d, J = 8.5); 8.54 (1 H, br. s);7.85 (2 H, d, J = 7.5);7.57 (2 H, t, J = 7.5); 7.52-7.46(1 H, m); 5.06 (1 H, d, J = 5.9);4.58-4.52 (1 H, m); 4.12-4.02 (2 H, m); 2.60 (1 H, br. t, J = 7.2);2.28-2.18 (1 H,m); 2.08-1.98 (1 H, m); 1.84 (1 H, t, J = 5.4);1.81-1.76(1 H, m); 1.73-1.60 (2 H, m); 1.38-1.20 (3 H, m); 1.25(3 H, s);1.23 (3 H, s); 1.16 (3 H, d, J = 6.2); 0.86 (6 H,d, J = 6.3); 0.81 (3 H,s). H.2.7

5-Phenyl-pyridine-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1H-NMR(DMSO-d6): 9.08 (1 H, s); 9.01 (1 H, br. s);8.68 (1 H, d, J = 8.5); 8.38(1 H, d, J = 8.3); 8.19 (1 H, d,J = 8.0); 7.88 (2 H, d, J = 7.4); 7.62(2 H, t, J = 7.3);7.58-7.52 (1 H, m); 5.31 (1 H, br. d, J = 4.3);4.55-4.49(1 H, m); 4.20-4.12 (2 H, m); 2.68 (1 H, br. t, J =7.2);2.32-2.22 (1 H, m); 2.13-2.04 (1 H, m); 1.95-1.82(2 H, m);1.79-1.65 (2 H, m); 1.45-1.27 (3 H, m); 1.30(3 H, s); 1.28 (3 H, s);1.17 (3 H, d, J = 6.0);0.90 (6 H, d, J = 6.4), 0.86 (3 H, s). H.2.8

4-Phenyl-pyridine-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1HNMR (DMSO-d6): 8.94 (1 H, br. s); 8.76 (1 H, d,J = 5.1); 8.67 (1 H, d, J= 8.5); 8.31 (1 H, s); 7.99(1 H, d, J = 5.1); 7.88 (2 H, d, J = 7.4);7.60-7.50(3 H, m); 5.25 (1 H, d, J = 4.8); 4.47 (1 H, dd, J = 8.4,4.1);4.14-4.06 (2 H, m); 2.62 (1 H, br. t, J = 8.0);2.26-2.16 (1 H, m);2.06-1.98 (1 H, m); 1.84 (1 H, t,J = 5.5); 1.83-1.76 (1 H, m); 1.73-1.59(2 H, m); 1.40-1.20 (3 H, m); 1.24 (3 H, s); 1.22 (3 H, s); 1.11 (3 H,d,J = 6.2); 0.84 (6 H, d, J = 6.5); 0.80 (3 H, s). H.2.9

Isoquinoline-1-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1H-NMR(DMSO-d6): 9.14 (1 H, d, J = 8.6); 8.96 (1 H,s); 8.75 (1 H, d, J = 8.2);8.60 (1 H, d, J = 5.5);8.11-8.05 (2 H, m); 7.84 (1 H, t, J = 7.5); 7.73(1 H, t,J = 7.5); 5.22 (1 H, d, J = 4.9); 4.51-4.46 (1 H, m);4.15-4.06(2 H, m); 2.64-2.57 (1 H, m); 2.24-2.15(1 H, m); 2.06-1.97 (1 H, m);1.83 (1 H, t, J = 5.0);1.82-1.75 (1 H, m); 1.74-1.55 (2 H, m);1.37-1.20(3 H, m); 1.24 (3 H, s); 1.21 (3 H, s); 1.16 (3 H, d,J = 6.0),0.85-0.78 (9 H, m). H.2.10

Isoquinoline-3-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1HNMR (DMSO-d6): 9.43 (1 H, s); 9.18 (1 H, s); 8.96(1 H, s); 8.78 (1 H, d,J = 8.3); 8.28-8.20 (2 H, m); 7.90-7.80 (2 H, m); 5.26 (1 H, d, J =4.6); 4.52-4.48 (1 H, m);4.11 (2 H, d, J = 7.0); 2.66-2.59 (1 H, m);2.25-2.15(1 H, m); 2.07-1.98 (1 H, m); 1.80-1.70 (2 H, m);1.65-1.60 (2H, m); 1.40-1.30 (3 H, m); 1.25 (3 H, s);1.22 (3 H, s); 1.13 (3 H, d, J= 6.1); 0.87-0.79(9 H, m) H.2.11

Quinoline-3-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1H-NMR(DMSO-d6): 9.31 (1 H, s); 9.00 (1 H, s);8.91 (1 H, s); 8.61 (1 H, d, J =8.3); 8.15-8.08 (2 H, m);7.89 (1 H, t, J = 7.6); 7.72 (1 H, t, J = 7.6);5.08 (1 H, d,J = 5.8); 4.58-4.52 (1 H, m); 4.12-4.00 (2 H, m); 2.59(1 H,br. t); 2.25-2.15 (1 H, m); 2.04-1.97 (1 H, m);1.86-1.80 (1 H, m);1.80-1.74 (1 H, m); 1.73-1.58 (2 H,m); 1.38-1.20 (3 H, m); 1.24 (3 H,s); 1.21 (3 H, s); 1.16(3 H, d, J = 6.4); 0.84 (6 H, d, J = 6.4); 0.80(3 H, s). H.1.12

5-(Thiophene-2-yl)pyridine-3-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1H-NMR(DMSO-d6): 9.06 (1 H, d, J = 1.9); 9.02 (1 H,s); 8.94 (1 H, d, J = 1.9);8.66 (1 H, d, J = 8.2); 8.43(1 H, t, J = 1.8); 7.77-7.70 (2 H, m);7.26-7.21 (1 H,m); 5.06 (1 H, d, J = 5.8); 4.53-4.48 (1 H, m); 4.10-4.09(2 H, m); 2.60-2.54 (1 H, m); 2.24-2.14 (1 H, m);2.05-1.96 (1 H, m);1.82 (1 H, t, J = 5.4); 1.80-1.74(1 H, m); 1.73-1.58 (2 H, m); 1.36-1.16(3 H, m); 1.23(3 H, s); 1.21 (3 H, s); 1.13 (3 H, d, J = 6.2); 0.86-0.82(6 H, m); 0.79 (3 H, s). H.2.13

5-Phenyl-2H-pyrazole-3-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1H-NMR(DMSO-d6): 13.6 (1 H, br.s); 9.03 (1 H, s);7.91 (1 H, br. s); 7.88 (2 H,d, J = 7.7); 7.57-7.50(2 H, m); 7.47-7.41 (1 H, m); 7.25 (1 H, br. s);5.23(1 H, br.s); 4.55-4.49 (1 H, m); 4.16 (1 H, d, J = 8.3);4.13-4.06 (1H, m); 2.69-2.62 (1 H, m); 2.31-2.22(1 H, m); 2.13-2.05 (1 H, m); 1.90(1 H, t, J = 5.5);1.87-1.82 (1 H, m); 1.79-1.66 (2 H, m); 1.44-1.25(3 H,m); 1.31 (3 H, s); 1.28 (3 H, s); 1.16 (3 H, d,J = 6.2); 0.91 (6 H, d, J= 6.5); 0.87 (3 H, s). H.2.14

1H-Indole-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1HNMR (DMSO-d6): 11.68 (1 H, s); 9.00 (1 H, s);8.17 (1 H, d, J = 8.5);7.65 (1 H, d, J = 8.0); 7.44(1 H, d, J = 8.2); 7.25 (1 H, s); 7.20 (1 H,t, J = 7.5);7.05 (1 H, t, J = 7.5); 5.08 (1 H, d, J = 5.9); 4.56-4.50(1H, m); 4.11-4.00 (2 H, m); 3.41-3.38 (1 H, m);2.62-2.55 (1 H, m);2.25-2.15 (1 H, m); 2.06-1.96(1 H, m); 1.86-1.75 (2 H, m); 1.75-1.59 (2H, m);1.36-1.26 (3 H, m); 1.24 (3 H, s); 1.22 (3 H, s); 1.15-1.07 (3 H,m); 0.87-0.79 (9 H, m). H.2.15

6-Phenyl-pyrimidine-4-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1H-NMR(DMSO-d6): 9.43 (1 H, s); 8.88 (1 H, br. s);8.70 (1 H, d, J = 8.5); 8.52(1 H, s); 8.33-8.28 (2 H, m);7.64-7.56 (3 H, m); 5.27 (1 H, d, J = 4.8);4.46 (1 H, dd,J = 7.9, 4.2); 4.16-4.07 (2 H, m); 2.69-2.62 (1 H,m);2.26-2.17 (1 H, m); 2.08-1.98 (1 H, m); 1.84 (1 H, t,J = 5.2);1.82-1.76 (1 H, m); 1.71-1.59 (2 H, m); 1.39-1.20 (3 H, m); 1.24 (3 H,s); 1.22 (3 H, s); 1.12 (3 H, d,J = 6.7); 0.84 (6 H, d, J = 6.4); 0.80(3 H, s). H.2.16

5-Methyl-1-phenyl-1H-pyrazole-4-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1H-NMR(DMSO-d6): 9.20 (1 H, br. s); 8.30 (1 H, s);7.91 (1 H, d, J = 8.5);7.66-7.52 (5 H, m); 5.14 (1 H, d,J = 6.1); 4.61-4.58 (1 H, m); 4.14-4.04(2 H, m); 2.62-2.55 (4 H, m); 2.30-2.20 (1 H, m); 2.12-2.03 (1 H,m);1.91-1.82 (2 H, m); 1.80-1.64 (2 H, m); 1.41 (1 H, d,J = 10.0);1.38-1.25 (2 H, m); 1.31 (3 H, s); 1.28(3 H, s); 1.17 (3 H, d, J = 6.3);0.94-0.89 (6 H, m);0.87 (3 H, s). H.2.17

2-Phenyl-thiazole-4-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1HNMR (DMSO-d6): 8.99-8.66 (1 H, m); 8.39 (1 H,s); 8.15 (1 H, d, J = 8.4);8.06-8.01 (2 H, m); 7.58-7.52 (3 H, m); 5.24 (1 H, d, J = 8.4);4.48-4.42 (1 H,m); 4.14-4.06 (2 H, m); 2.65-2.58 (1 H, m); 2.26-2.16(1H, m); 2.08-2.00 (1 H, m); 1.85 (1 H, t, J = 5.4);1.80-1.75 (1 H, m);1.73-1.59 (2 H, m); 1.41-1.30(2 H, m); 1.25 (3 H, s); 1.22 (3 H, s);1.20-1.15 (1 H,m); 1.12 (3 H, d, J = 5.3); 0.85 (6 H, d, J = 6.5);0.80(3 H, s). H.2.18

6-(Thiophene-2-yl)pyridine-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1HNMR (DMSO-d6): 8.93 (1 H, br. s); 8.58 (1 H, d,J = 8.2); 8.13 (1 H, dAB, J = 7.9); 8.04 (1 H, d AB,J = 7.9); 7.95-7.88 (2 H, m); 7.73 (1 H,d, J = 4.7);7.22 (1 H, t, J = 4.2); 5.26 (1 H, d, J = 4.4); 4.44 (1H,dd, J = 8.0, 4.1); 4.16-4.05 (2 H, m); 2.61 (1 H, br. t,J = 6.6);2.25-2.15 (1 H, m); 2.08-1.98 (1 H, m); 1.84(1 H, t, J = 5.2); 1.82-1.74(1 H, m); 1.74-1.59 (2 H,m); 1.41-1.20 (3 H, m); 1.24 (3 H, s); 1.22 (3H, s);1.12 (3 H, d, J = 6.5); 0.84 (6 H, d, J = 6.4); 0.80(3 H, s).H.2.19

6-Butyl-pyridine-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]H.2.20

Pyridine-1-oxo-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]1H-NMR(DMSO-d6): 11.54 (1 H, d, J = 7.6, NH);8.96 (1 H, br. s); 8.46 (1 H, d,J = 6.3); 8.22 (1 H, d,J = 7.6); 7.68-7.57 (2 H, m); 5.17 (1 H, d, J =4.2);4.42-4.47 (1 H, m); 4.13-4.6 (2 H, m); 2.57 (1 H, br. t,J = 7.3);2.25-2.16 (1 H, m); 2.07-1.98 (1 H, m); 1.84(1 H, t, J = 5.6); 1.82-1.77(1 H, m); 1.73-1.60 (2 H,m); 1.38-1.20 (3 H, m); 1.25 (3 H, s); 1.23 (3H, s);1.12 (3 H, d, J = 6.2); 0.85-0.80 (9 H, m). H.2.21

Pyridine-1-oxo-3-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]

Example J.1 Preparation of 2-Pyrazinecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-

2-Pyrazinecarboxylic acid (163 mg, 1.31 mmol, 1.1 eq.) was dissolved indry DMF (6 ml). TBTU (420 mg, 1.11 mmol, 1.1 eq.) was added to thesolution at r.t. under nitrogen. The resulting mixture was stirred for10 min and then cooled to 0-5° C. NMM (0.4 ml, 3.57 mmol, 3 eq.) and(2S)-2-amino-3-[(4-methylbenzoyl)amino]propanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,hydrochloride salt (600 mg, 1.19 mmol, 1 eq.) of Example C.4 were thenadded and the resulting mixture was stirred at r.t. for 5 h. Thesolution was poured into water (50 ml) and citric acid 2% (30 ml), thenthe aqueous suspension was extracted with ethyl acetate (40 ml). Theorganic solvent was washed with a solution of sodium bicarbonate 2% (30ml) and NaCl 2% (50 ml). The organic phase was dried over anhydroussodium sulphate, filtered, and evaporated. The resulting crude waspurified by silica gel chromatography (eluent: ethyl acetate 100%). Thecollected fractions were evaporated under reduced pressure to a foamthat was resuspended in diethyl ether (20 ml) for 30 min. The suspensionwas filtered and dried to give 330 mg of white foam. Yield 73%.

¹H NMR (DMSO-d₆): δ 9.14 (1H, s); 8.95 (1H, d); 8.9 (1H, d); 8.8 (1H,d); 8.78 (1H, d); 8.4 (1H, m); 7.7 (2H, d); 7.2 (2H, d); 4.8 (1H, q);4.05 (1H, d); 3.65 (2H, m); 2.7 (1H, m); 2.35 (3H, s); 2.2 (1H, m); 2.05(1H, m); 1.80 (2H, m); 1.60 (2H, m); 1.3-1.0 (10H) m); 0.8 (9H, m).

Example J.2 Preparation of Further Compounds of the Invention

Further compounds of the invention are listed below which can be madeaccording to procedures analogous to those described for Example J.1using the appropriate carboxylic acid such as described in Example M.1.Those compounds listed below which are characterized by NMR data wereactually prepared.

Ex # Structure Chemical Name and Analytical Data J.2.1

6-phenyl-2-pyridinocarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-1HNMR (DMSO-d6): 9.14 (1 H, d); 8.90 (1 H, d); 8.5(1 H, t); 8.35 (2 H, d);8.18 (1 H, d); 8.1 (1 H, t); 7.95(1 H, d); 7.75 (2 H, d); 7.55 (3 H, m);7.2 (2 H, d); 4.75(1 H, m); 4.15 (1 H, d); 3.7 (2 H, m); 2.30 (3 H, s);2.2(1 H, m); 2.05 (1 H, m); 1.80 (2 H, m); 1.60 (2 H, m);1.3-1.0 (6 H,m); 0.8 (6 H, m). J.2.2

5-butyl-2-pyridinocarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.3

2-pyridinocarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-1H-NMR(DMSO-d6): 8.95 (1 H, d, J = 8.1);8.89 (1 H, br. d, J = 3.3); 8.73 (1 H,d, J = 4.5);8.48 (1 H, t, J = 5.7); 8.10-8.01 (2 H, m);7.74 (2 H, d, J =7.9); 7.68 (1 H, t,J = 5.3); 7.29 (2 H, d, J = 7.9); 4.87 (1 H, dd, J =7.1,13.3); 4.18 (1 H, d, J = 8.3); 3.78-3.64 (2 H, m); 2.78-2.70 (1 H,m); 2.39 (3 H, s); 2.30-2.20 (1 H, m); 2.13-2.04 (1 H, m); 1.92-1.81 (2H, m); 1.72-1.63 (2 H, m);1.46-1.29 (3 H, m); 1.29 (3 H, s); 1.27 (3 H,s); 0.89-0.83 (9 H, m). J.2.4

3-pyridinocarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-1H-NMR(DMSO-d6): 9.07 (1 H, s); 8.94 (2 H, m);8.78 (1 H, d, J = 4.8); 8.55 (1H, t, J = 4.8);8.24 (1 H, d, J = 7.6); 7.77 (2 H, d, J = 7.9);7.59 (1 H,dd, J = 7.8, 5.0); 7.31 (2 H, d, J = 7.9);4.86 (1 H, dd, J = 7.7, 13.6);4.17 (1 H, d,J = 8.0); 3.80-3.67 (2 H, m); 2.74-2.66 (1 H, m);2.40 (3 H,s); 2.30-2.22 (1 H, m); 2.12-2.06 (1 H, m);1.89 (1 H, t, J = 5.4);1.87-1.81 (1 H, m); 1.75-1.65 (2 H,m); 1.45-1.29 (3 H, m); 1.30 (3 H,s); 1.28 (3 H, s);0.89-0.83 (9 H, m). J.2.5

Quinoline-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-1HNMR (DMSO-d6): 9.07 (1 H, d, J = 8.0); 8.92 (1 H,br. s); 8.58 (1 H, d, J= 8.6); 8.49 (1 H, t, J = 5.4);8.17-8.06 (3 H, m); 7.91 (1 H, t, J =7.6);7.77-7.69 (3 H, m); 7.23 (2 H, d, J = 7.8);4.84 (1 H, dd, J = 13.9,7.1); 4.14 (1 H, d,J = 8.3); 3.78-3.64 (2 H, m); 2.72-2.65 (1 H, m);1.32(3 H, s); 2.24-2.15 (1 H, m); 2.08-1.99 (1 H, m);1.86-1.76 (2 H, m);1.68-1.60 (2 H, m); 1.43-1.22(3 H, m); 1.25 (3 H, s); 1.21 (3 H, s);0.83-0.76(9 H, m). J.2.6

Quinoxaline-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-1H-NMR(DMSO-d6): 9.48 (1 H, s); 8.13 (1 H, d,J = 8.0); 8.88 (1 H, br. d, J =3.5); 8.50 (1 H, t,J = 5.7); 8.26-8.20 (2 H, m); 8.06-8.01 (2 H, m);7.73(2 H, d, J = 7.9); 7.25 (2 H, d, J = 7.9); 4.88 (1 H, q,J = 6.8);4.16 (1 H, d, J = 8.1); 3.76 (2 H, t,J = 6.0); 2.75-2.67 (1 H, m); 2.34(3 H, s); 2.26-2.17(1 H, m); 2.09-2.01 (1 H, m); 1.86 (1 H, t, J =5.4);1.83-1.78 (1 H, m); 1.70-1.62 (2 H,m); 1.43-1.25 (3 H, m); 1.27 (3H, s); 1.23 (3 H, s);0.85-0.79 (9 H, m). J.2.7

6-phenyl-2-pyrazinocarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-1HNMR (DMSO-d6): 9.5 (1 H, s); 9.22 (1 H, d); 9.1(1 H, s); 8.82 (1 H, bs);8.6 (1 H, m); 8.4 (2 H, d);7.75 (2 H, d); 7.6 (3 H, m); 7.2 (2 H, d);4.75(1 H, m); 4.1 (1 H, d), 3.75 (2 H, m); 2.35 (3 H, s);2.7 (1 H, m);2.2 (1 H, m); 2.05 (1 H, m);1.80 (2 H, m); 1.60 (2 H, m);1.3-1.0 (10 H,m); 0.8 (9 H, m). J.2.8

5-phenyl-2-pyrazinocarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-1HNMR (DMSO-d6): 9.35 (1 H, s); 9.22 (1 H, s);8.95 (1 H, d); 8.85 (1 H,d); 8.45 (1 H, t); 8.25(1 H, d); 7.7 (2 H, d); 7.6 (3 H, m); 7.25 (2 H,d);4.85 (1 H, q); 4.1 (1 H, d); 3.7 (2 H, m); 2.7 (1 H, m);2.35 (3 H,s); 2.2 (1 H, m); 2.05 (1 H, m); 1.80 (2 H,m); 1.60 (2 H, m); 1.3-1.0 (9H, m); 0.8 (9 H, m). J.2.9

5-Phenyl-pyridine-3-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.10

5-Phenyl-pyridine-2-carboxamideN-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-,J.2.11

4-Phenyl-pyridine-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.12

Isoquinoline-1-carboxamideN-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-,J.2.13

Isoquinoline-3-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.14

Quinoline-3-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.15

5-(Thiophene-2-yl)-pyridine-3-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.16

5-Phenyl-2H-pyrazole-3-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.17

1H-Indole-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.18

6-Phenyl-pyrimidine-4-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.19

5-Methyl-1-phenyl-1H-pyrazole-4-carboxamideN-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.20

2-Phenyl-thiazole-4-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.21

6-(Thiophene-2-yl)pyridine-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-1HNMR (DMSO-d6): 8.90-8.86 (1 H, m); 8.84 (1 H,d, J = 7.7); 8.47 (1 H, t,J = 5.8); 8.07-7.98 (3 H, m);7.87 (1 H, d, J = 7.3); 7.77-7.70 (3 H, m);7.27-7.20(3 H, m); 4.77 (1 H, m); 4.15 (1 H, d, J = 7.7); 3.74-3.64 (2H, m); 2.72-2.65 (1 H, m); 2.33 (3 H, s); 2.24-2.15 (1 H, m); 2.09-2.00(1 H, m); 1.84 (1 H, t,J = 5.3); 1.80-1.75 (1 H, m); 1.68-1.59 (2 H,m);1.42-1.32 (2 H, m); 1.29-1.23 (1 H, m); 1.26 (3 H, s);1.21 (3 H, s);0.83-0.77 (9 H, m). J.2.22

6-Butyl-pyridine-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.23

6-morpholino-3-pyridinocarbonylamino,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-1HNMR (DMSO-d6): 8.9 (1 H, d); 8.90 (1 H, d); 8.65(1 H, d); 8.45 (2 H, m);8.0 (1 H, d); 7.75 (2 H, d); 7.3(2 H, d); 6.95 (1 H, d); 4.8 (1 H, q);4.15 (1 H, d);3.75 (4 H, m); 3.70 (2 H, m); 3.6 (4 H, m); 2.6 (1 H,m);2.35 (3 H, s); 2.2 (1 H, m); 1.85 (2 H, m); 1.65(2 H, m); 1.3- 1.0 (8 H,m); 0.85 (9 H, m). J.2.24

Pyridine-1-oxo-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-J.2.25

Pyridine-1-oxo-3-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-

Example K.1 Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-phenyl-pyrazine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]

A mixture of 6-phenyl-pyrazine-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]of Example H.1 (235 mg, 0.428 mmol) and 2-methylpropylboronic acid (131mg, 1.28 mmol) was dissolved in methanol (3 ml). Then 2 N aqueous HCl(0.6 ml) and hexane (3 ml) were added. The resulting heterogeneousmixture was vigorously stirred at room temperature for 16 hours. Thelayers were then separated and the methanolic phase was concentrated todryness. The residue was purified by elution on a SPE-SI normal phasecartridge (20 g SiO₂) using first ethyl acetate, then methanol. Theproduct was then dissolved in ethyl acetate containing 4% methanol (100ml) and washed with a 10% solution of NaHCO₃. The phases were separatedand the organic layer was dried over sodium sulfate and concentrated todryness. The product was obtained as a white solid (120 mg, 70% yield).

¹H NMR (MeOH-d₄): δ 9.40 (1H, s); 9.22 (1H, s); 8.29-8.25 (2H, m);7.61-7.58 (3H, m); 4.80 (1H, d, J=6.9); 4.47-4.41 (1H, m); 2.78 (1H, t,J=7.5); 1.71-1.61 (1H, m); 1.37 (2H, t, J=7.3); 1.31 (3H, d, J=6.4);0.93 (3H, s); 0.91 (3H, s).

Example K.2 Preparation of Further Compounds of the Invention

Further compounds of the invention are listed below which can be madeaccording to procedures analogous to those described for Example K.1using the appropriate boronic ester. Those compounds listed below whichare characterized by NMR data were actually prepared.

Ex # Structure Chemical Name and Analytical Data K.2.1

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(pyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]K.2.2

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(pyridine-3-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]K.2.3

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(quinoline-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 8.41 (1 H, m); 8.15-8.09 (2 H, m);7.93 (1 H, m); 7.77 (1H, t, J = 7.7); 7.62 (1 H, t, J = 7.5);4.69 (1 H, d, J = 3.2); 4.36-4.29(1 H, m); 2.66 (1 H, t,J = 7.6); 1.59-1.50 (1 H, m); 1.25, t, J = 7.3);1.20 (3 H, d,J = 6.4); 0.81 (3 H, s); 0.79 (3 H, s) K.2.4

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(quinoxaline-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 9.53 (1 H, s); 8.30-8.25 (1 H, m);8.22-8.17 (1 H, m);8.02-7.94 (2 H, m); 4.80 (1 H, d,J = 3.1); 4.46-4.39 (1 H, m); 2.76 (1H, t, J = 7.6); 1.69-1.58(1 H, m); 1.35 (2 H, t, J = 7.3); 1.30 (3 H, d,J = 6.4); 0.89(6 H, d, J = 6.5). K.2.5

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(5-phenyl-pyrazine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 9.29 (1 H, s); 9.23 (1 H, s); 8.23-8.18 (2 H, m);7.60-7.54 (3 H, m); 4.75 (1 H, d, J = 6.9);4.44-4.35 (1 H, m); 2.76 (1H, t, J = 6.7); 1.72-1.58 (1 H,m); 1.36 (2 H, t, J = 7.3); 1.28 (3 H, d,J = 6.4); 0.91 (6 H, d,J = 6.5). K.2.6

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(5-phenyl-pyridine-3-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 9.04 (1 H, s); 9.01 (1 H, s); 8.58(1 H, s); 7.78 (2 H, d,J = 7.7); 7.59-7.53 (2 H, m); 7.52-7.46 (1 H, m); 4.82 (1 H, d, J =4.5); 4.38-4.31 (1 H, m);2.80 (1 H, t, J = 7.6); 1.73-1.62 (1 H, m);1.38 (2 H, t,J = 7.3); 1.32 (3 H, d, J = 6.3); 0.94 (6 H, d, J = 6.5).K.2.7

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(5-phenyl-pyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]M.p.190-195° C.1H NMR (MeOH-d4): 8.98 (1 H, s); 8.27-8.16 (2 H, m);7.75 (2H, d, J = 7.3); 7.56-7.51 (2 H, m); 7.50-7.44 (1 H,m); 4.74 (1 H, br. d,J = 3.0); 4.42-4.34 (1 H, m); 2.75 (1 H,t, J = 7.5); 1.70-1.59 (1 H, m);1.35 (2 H, t, J = 7.3); 1.27(3 H, d, J = 6.3); 0.93-0.89 (6 H, m). K.2.8

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(4-phenyl-pyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 8.75 (1 H, d, J = 4.8); 8.41 (1 H, s);7.91 (1 H, d, J =4.9); 7.82 (2 H, d, J = 7.5); 7.60-7.47 (3 H,m); 4.77 (1 H, br. s);4.45-4.36 (1 H, m); 2.77 (1 H, t,J = 7.5); 1.72-1.61 (1 H, m); 1.37 (2H, t, J = 7.3); 1.29 (3 H,d, J = 6.3); 0.92 (6 H, d, J = 6.3). K.2.9

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(isoquinoline-1-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 9.02 (1 H, d, J = 8.7); 8.47 (1 H, d,J = 5.5); 7.92-7.88(2 H, m); 7.71 (1 H, t, J = 7.5); 7.62 (1 H,t, J = 7.7); 4.71 (1 H, d, J= 3.1); 4.33-4.25 (1 H, m); 2.65(1 H, t, J = 7.5); 1.61-1.49 (1 H, m);1.26 (2 H, t, J = 7.7);1.21 (3 H, d, J = 6.3); 0.80 (6 H, d, J = 6.5).K.2.10

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(isoquinoline-3-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 9.35 (1 H, s); 8.57 (1 H, s); 8.20(1 H, d, J = 8.0); 8.11(1 H, d, J = 8.0); 7.91-7.79 (2 H, m);4.79 (1 H, s); 4.45-4.35 (1 H, m);2.75 (1 H, t, J = 7.3);1.55-1.51 (1 H, m); 1.35 (2 H, t, J = 7.3); 1.29(3 H, d,J = 6.4); 0.91 (3 H, s); 0.91 (3 H, s) K.2.11

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(quinoline-3-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 9.20 (1 H, s); 8.82 (1 H, s); 8.01(2 H, t, J = 7.5); 7.82(1 H, t, J = 7.7); 7.63 (1 H, t, J = 7.6);4.72 (1 H, br. s); 4.28-4.24(1 H, m); 2.68 (1 H, t, J = 7.6);1.62-1.50 (1 H, m); 1.27 (2 H, t, J =7.3); 1.22 (3 H, d,J = 6.3); 0.82 (6 H, d, J = 6.5). K.2.12

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(5-(thiophene-2-yl)pyridine-3-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 9.03 (1 H, s); 8.96 (1 H, s); 8.55(1 H, s); 7.66 (1 H, d,J = 3.2); 7.59 (1 H, d, J = 4.8); 7.25-7.20 (1 H, m); 4.81 (1 H, d, J =4.6); 4.38-4.30 (1 H, m);2.79 (1 H, t, J = 7.6); 1.73-1.62 (1 H, m);1.38 (2 H, t,J = 7.3); 1.31 (3 H, d, J = 6.4); 0.94 (6 H, d, J = 6.5).K.2.13

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(5-phenyl-2H-pyrazole-3-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]M.p.232-236° C.1H NMR (MeOH-d4): 7.75 (2 H, 1 br. d, J = 6.8); 7.52-7.45 (2H, m); 7.44-7.38 (1 H, m); 7.10 (1 H, br. s); 4.77(1 H, br. d, J = 2.7);4.39-4.32 (1 H, m); 2.77 (1 H, t,J = 7.4); 1.74-1.62 (1 H, m); 1.37 (2H, t, J = 7.3); 1.29 (3 H,d, J = 6.4); 0.95-0.92 (6 H, m). K.2.14

Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(1H-indole-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1H NMR(MeOH-d4): 7.64 (1 H, d, J = 8.0); 7.45 (1 H, d,J = 8.3); 7.24 (1 H, t,J = 8.0); 7.22 (1 H, bs); 7.08 (1 H, d,J = 7.5); 4.79 (1 H, d, J = 3.6);4.37-4.30 (1 H, m); 2.75(1 H, t, J = 7.3); 1.71-1.59 (1 H, m); 1.36 (2H, t, J = 7.3);1.28 (3 H, d, J = 6.3); 0.94-0.89 (6 H, m). K.2.15

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-phenyl-pyrimidine-4-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 9.34 (1 H, d, J = 0.9); 8.56 (1 H, d,J = 0.9); 8.28-8.23(2 H, m); 7.61-7.54 (3 H, m); 4.75 (1 H,d, J = 3.2); 4.43-4.35 (1 H, m);2.76 (1 H, t, J = 7.6); 1.70-1.59 (1 H, m); 1.35 (2 H, t, J = 7.3); 1.28(3 H, d, J = 6.4);0.91 (3 H, d, J = 6.5); 0.90 (3 H, d, J = 6.5). K.2.16

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(5-Methyl-1-phenyl-1H-pyrazole-4-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 8.18 (1 H, s); 7.63-7.52 (3 H, m);7.51-7.46 (2 H, m);4.76 (1 H, d, J = 3.4); 4.36-4.29 (1 H,m); 2.77 (1 H, t, J = 7.6);1.73-1.62 (1 H, m); 1.38 (2 H, t,J = 7.2); 1.30 (3 H, d, J = 6.4); 0.95(6 H, d, J = 6.4). K.2.17

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(2-phenyl-thiazole-4-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 8.28 (1 H, s); 8.10-8.04 (2 H, m);7.54-7.49 (3 H, m);4.74 (1 H, d, J = 3.0); 4.44-4.35 (1 H,m); 2.75 (1 H, t, J = 7.6);1.69-1.59 (1 H, m); 1.35 (2 H, t,J = 7.3); 1.29 (3 H, d, J = 6.4); 0.91(6 H, d, J = 6.5). K.2.18

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-(thiophene-2-yl)pyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 8.06-7.95 (3 H, m); 7.84 (1 H, d,J = 3.7); 7.58 (1 H, d,J = 5.0); 7.21-7.17 (1 H, m); 4.71(1 H, br. d, J = 3.0); 4.46-4.39 (1 H,m); 2.76 (1 H, t,J = 7.6); 1.71-1.61 (1 H, m); 1.37 (2 H, t, J = 7.3);1.32 (3 H,d, J = 6.4); 0.92 (6 H, d, J = 6.6). K.2.19

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-butyl-pyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]K.2.20

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(pyridine-1-oxo-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 8.45 (1 H, d, J = 6.0); 8.36 (1 H,dd, J = 7.6, 2.5);7.74-7.64 (2 H, m); 4.73 (1 H, br. d,J = 3.0); 4.44-4.37 (1 H, m); 2.75(1 H, t, J = 7.6); 1.72-1.61(1 H, m); 1.40-1.33 (2 H, m); 1.31 (3 H, d,J = 6.3); 0.92(6 H, d, J = 6.5). K.2.21

Boronic acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(pyridine-1-oxo-3-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]

Example L.1 Preparation of Boronic acid,[(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(pyrazinocarbonylamino)]-1-oxopropyl]amino]-3-methylbutyl]

2-Pyrazinecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoylamide)ethyl]-,of Example J.1 (450 mg, 0.78 mmol, 1 eq.), was dissolved in methanol (4ml), and n-hexane (4 ml). To this solution, isobutylboronic acid (120mg, 1.17 mmol, 1.5 eq,) and HCl 4N 1,4-dioxane (0.3 ml, 1.17 mmol, 1.5eq.) were added. The resulting biphasic mixture was stirred at roomtemperature for 48 h. The n-hexane was removed, and the resulting themethanolic solution was washed with n-hexane (2 ml) and evaporated underreduced pressure. The crude was redissolved in dichloromethane (250 ml)and washed with sodium bicarbonate 2%. The organic phase was dried overanhydrous sodium sulphate and evaporated under reduced pressure to givea foam. The foam was stirred in diethyl ether overnight, then wasfiltered, to give a white powder. Yield 44%, 150 mg.

Analytical data: M.p. 132° C.-135° C. A.E. calculated: C (57.16%), H(6.40%), N (15.87%). found C (56.56%), N (15.26%).

¹H NMR (DMSO-d₆): δ 9.25 (1H, s); 8.82 (1H, d); 8.72 (1H, d); 7.75 (2H,d); 7.25 (2H, d); 5.05 (1H, t); 3.95 (2H, m); 2.8 (1H, t); 2.4 (3H, s);1.6 (1H, m); 1.35 (2H, m); 1.60 (2H, m); 1.3-1.0 (9H, m); 0.85 (6H, dd).

Example L.2 Preparation of Further Compounds of the Invention

Further compounds of the invention are listed below which can be madeaccording to procedures analogous to those described for Example L.1using the appropriate boronic ester. Those compounds listed below whichare characterized by NMR data were actually prepared.

Ex # Structure Chemical Name and Analytical Data L.2.1

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(6-phenyl-pyridine-2-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]1HNMR (DMSO-d6): 8.3 (2 H, d); 8.11 (1 H, m);8.07 (2 H, d); 7.85 (2 H, d);7.5 (2 H, d); 7.25 (2 H, d);5.0 (1 H, t); 4.01-3.98 (2 H, m); 2.8 (1 H,t); 2.4 (3 H,s); 1.6 (1 H, m); 1.35 (2 H, m); 0.9 (6 H, dd). L.2.2

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(5-butyl-pyridine-2-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 8.52 (1 H, s); 7.97 (1 H, d,J = 8.0); 7.78 (1 H, d, J =7.9); 7.71 (2 H,d,J = 7.8); 7.26(2 H, d, J = 7.8); 5.01 (1 H, t, J =6.2); 3.89 (2 H,d,J = 6.2); 2.80-2.70 (3 H, m); 2.38 (3 H, s); 1.70-1.53(3 H, m); 1.44-1.27 (4 H, m); 0.96 (3 H, t, J = 7.3);0.88 (3 H, d, J =6.5); 0.84 (3 H, d, J = 6.5). L.2.3

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(pyridine-2-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]1HNMR (MeOH-d4): 8.70 (1 H, br. s); 8.86 (1 H, d,J = 7.7); 8.0 1-7.94 (1H, m); 7.73 (2 H, d, J = 7.2); 7.63-7.55 (1 H, m); 7.28 (2 H, d, J =7.7); 5.04 (1 H, t, J = 6.0);3.91 (2 H, br. d, J = 5.8); 2.79 (1 H, t, J= 7.5); 2.40 (3 H,s); 1.66-1.54 (1 H, m); 1.34 (2 H, br. t, J = 7.1);0.90(3 H, d, J = 6.5); 0.86 (3 H, d, J = 6.6). L.2.4

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(pyridine-3-carbonyl)amino]-1-oxopropyl]amino]-3-methyibutyl]M.p.220-222° C.1H NMR (MeOH-d4): 9.03 (1 H, s); 8.71 (1 H, d,J = 4.6); 8.28(1 H, d, J = 8.0); 7.74 (2 H, d, J = 7.9); 7.57(1 H, dd, J = 7.8, 5.0);7.28 (2 H, d, J = 7.9); 4.98 (1 H, t,J = 6.4); 3.95 (1 H, dd, J = 13.8,6.5, AB); 3.83 (1 H, dd,J = 13.8, 6.5, AB); 2.77 (1 H, t, J = 7.5); 2.39(3 H, s);1.63-1.52 (1 H, m); 1.37-1.26 (2 H, m); 0.88 (3 H, d,J = 6.5);0.83 (3 H, d, J = 6.5). L.2.5

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(quinoline-2-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]M.p.235-237° C.1H NMR (MeOH-d4): 8.82 (1 H, br. t, J = 5.7); 8.47(1 H, d, J= 8.5); 8.23 (1 H, d, J = 8.5); 8.15 (1 H, d,J = 8.5); 8.00 (1 H, d, J =8.2); 7.86 (1 H, t, J = 7.6); 7.75(2 H, d, J = 7.9); 7.70 (1 H, t, J =7.6); 7.26 (2 H, d,J = 7.9); 5.08 (1 H, t, J = 6.2); 4.05-3.91 (2 H, m);2.79(1 H, t, J = 7.7); 2.38 (3 H, s); 1.67-1.56 (1 H, m); 1.34(2 H, br.t, J = 7.3); 0.88 (3 H, d, J = 6.5); 0.85 (3 H, d,J = 6.5). L.2.6

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(quinoxaline-2-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]M.p.160-1602° C.1H NMR (MeOH-d4): 9.48 (1 H, s), 8.34-8-29 (1 H,m);8.21-8.16 (1H, m); 8.01-7.94 (2 H, m); 7.74 (2 H,d, J = 7.9); 7.27 (2 H,d, J = 7.9); 5.08 (1 H, t, J = 6.1);4.05-3.93 (2 H, m); 2.79 (1 H, t, J= 7.4); 2.38 (3 H, s);1.66-1.55 (1 H, m); 1.35 (2 H, t, J = 7.3); 0.89(3 H, d,J = 6.5); 0.85 (3 H, d, J = 6.5). L.2.7

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(6-phenyl-2-pyrazinocarbonylamino)]-1-oxopropyl]amino]-3-methylbutyl1HNMR (DMSO-d6): 9.35 (1 H, s); 9.11 (1 H, s); 8.4(2 H, d); 7.80 (2 H, d);7.6 (3 H, m); 7.25 (2 H, d); 5.0(1 H, t); 4.01-3.98 (2 H, m); 2.8 (1 H,t); 2.35 (3 H, s);1.6 (1 H, m); 1.35 (2 H, m); 0.9 (6 H, dd). L.2.8

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(5-phenyl-2-pyrazinocarbonylamino)]-1-oxopropyl]amino]-3-methylbutyl1HNMR (DMSO-d6): 9.25 (2 H, d); 8.2 (2 H, d); 7.75(2 H, d); 7.65 (3 H, m);7.25 (2 H, d); 5.05 (1 H, t); 3.95(2 H, m); 2.8 (1 H, t); 2.35 (3 H, s);1.6 (1 H, m); 1.35(2 H, m); 0.9 (6 H, dd). L.2.9

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(5-phenyl-pyridine-3-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.10

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(5-phenyl-pyridine-2-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.11

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(4-phenyl-pyridine-2-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.12

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(isoquinoline-1-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.13

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(isoquinoline-3-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.14

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(quinoline-3-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.15

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(5-(thiophene-2-yl)pyridine-3-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.16

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(5-phenyl-2H-pyrazole-3-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.17

Boronic acid, [(1R)-1-[[(2 S)-3-[(4-methylbenzoyl)amino]-2-[(1H-indole-2-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl] L.2.18

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(6-phenyl-pyrimidine-4-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.19

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(5-Methyl-1-phenyl-1H-pyrazole-4-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.20

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(2-phenyl-thiazole-4-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.21

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(6-(thiophene-2-yl)pyridine-2-carbonyl)]-1-oxopropyl]amino]-3-methylbutylM.p.158-160° C.1H NMR (MeOH-d4): 8.01 (1 H, d, J = 3 .5); 7.98-7.92(3 H, m);7.81 (2 H, d, J = 7.9); 7.55 (1 H, d, J = 4.9); 7.28(2 H, d, J = 7.9);7.19 (1 H, t, J = 4.3); 5.02 (1 H, t, J = 5.2);4.10-4.02 (1 H, m);3.97-3.88 (1 H, m); 2.80 (1 H, t,J = 7.6); 2.40 (3 H, s); 1.67-1.56 (1H, m); 1.36 (2 H, t,J = 7.3); 0.90 (3 H, d, J = 6.6); 0.87 (3 H, d, J =6.6). L.2.22

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(6-butyl-pyridine-2-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.23

Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(6-morpholino-3-pyridinocarbonylamino)]-1-oxopropyl]amino]-3-methylbutyl1HNMR (DMSO-d6): 8.5 (1 H, s); 8.3 (1 H, d); 7.7(2 H, d); 7.35 (1 H, d);7.30 (2 H, d); 5.0 (1 H, t); 4.01-3.75 (10 H, m); 2.8 (1 H, t); 2.4 (3H, s); 1.6 (1 H, m);1.35 (2 H, m); 0.9 (6 H, dd). L.2.24

Boronic acid, [(1R)-1-[[(2 S)-3-[(4-methylbenzoyl)amino]-2-[(pyridine-1-oxo-2-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]L.2.25

Boronic acid, [(1R)-1-[[(2 S)-3-[(4-methylbenzoyl)amino]-2-[(pyridine-1-oxo-3-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]

Example M.1 Preparation/Source of Carboxylic Acids

Carboxylic acids suitable for preparing compounds of the inventionaccording to, for example, the procedures of Examples H.1 and J.1 can beobtained commercially or prepared according to routine methods or knownsynthetic procedures. For example, 6-phenyl-pyrazine-2-carboxylic acidand 5-phenyl-pyrazine-2-carboxylic acid were prepared according to theprocedure described in Litmanowitsch et al. CH458361.6-Butyl-pyridine-2-carboxylic acid was prepared via a Reissert-Kaufmantype reaction according the procedures described by Honma et al. in J.Med. Chem., 1984, 25, 125-128 or Nakashima et al., Ykugaku Zasshi, 1958,78, 666-670 (Chem. Abstr. 1958, 18399). Compounds6-phenyl-2-pyridinecarboxylic acid and6-(thiophene-2-yl)pyridine-2-carboxylic acids were prepared accordingthe procedure described by Gong et al. in Synlett, 2000, (6), 829-831.

Utility Methods and Compositions

Compounds of the present invention can inhibit the activity ofproteasome, leading to the inhibition or blocking of a variety ofintracellular functions with which the proteasome is directly orindirectly associated. For example, proteasome inhibitors can modulate,such as induce, apoptosis in a cell. In some embodiments, the compoundsherein can kill tumor cells by induction of apoptosis. Thus, the presentcompounds can be used to treat cancer, tumors or other proliferativedisorders.

In further embodiments, inhibition of proteasome function by compoundsof the invention can inhibit the activation or processing oftranscription factor NF-κB. This protein plays a role in the regulationof genes involved in the immune and inflammatory responses as well as incell viability. Inhibition of proteasome function can also inhibit theubiquitination/proteolysis pathway. This pathway catalyzes, inter alia,selective degradation of highly abnormal proteins and short-livedregulatory proteins. In some embodiments, compounds of the invention canprevent the degradation of p53 which is typically degraded by theubiquitin-dependent pathway. The ubiquitination/proteolysis pathway alsois involved in the processing of internalized cellular or viral antigensinto antigenic peptides that bind to MHC-I molecules. Thus, thecompounds of the invention can be used to reduce the activity of thecytosolic ATP-ubiquitin-dependent proteolytic system in a number of celltypes.

Accordingly, the usefulness of such compounds can include therapeutics,such as the treatment of various diseases or disorders associated withproteasome. The methods include administering a therapeuticallyeffective amount of a compound of the invention, or composition thereof,to a mammal, such as a human having a disease or disorder associatedwith proteasome. The phrase “therapeutically effective amount” refers toan amount sufficient to prevent, alleviate, or ameliorate anyphenomenon, such as a cause or symptom, known in the art to beassociated with the disease or disorder.

Treatable diseases or disorders (abnormal physical conditions) can beassociated with either normal or abnormal activities of proteasome, suchas the regulation of apoptosis. Numerous diseases or disorders that areassociated with proteasome, or that are desirably treated by inductionof apoptosis, are known and include, for example, various cancers andtumors including those associated with skin, prostate, colorectal,pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscletissues. Preferred tumors that can be treated with proteasome inhibitorsinclude, but are not limited to hematological tumors, such as, forexample, leukemias, lymphomas, non-Hodgkin lymphoma, myeloma, multiplemyeloma, as well as solid tumors such as, for example, colorectal,mammary, prostate, lung, and pancreas tumors. In order to elicittherapeutic effects, the proteasome inhibitors can be administered topatients as single agents or in combination with one or more antitumoror anticancer agent and/or radiotherapy. Examples of other anti-tumor oranti-cancer agents which can be advantageously administeredconcomitantly with a proteasome inhibitor include but are not limitedto, adriamycin, daunomycin, methotrexate, vincristin, 6-mercaptopurine,cytosine arabinoside, cyclophosphamide, 5-FU, hexamethylmelamine,carboplatin, cisplatin, idarubycin, paclitaxel, docetaxel, topotecan,irinotecam, gemcitabine, L-PAM, BCNU and VP-16. Methods for determiningapoptosis in vitro are well known in the art and kits are availablecommercially. See for example the Apo-ONE™ Homogeneous Caspase-3/7 Assayfrom Promega Corporation, Madison Wis., USA (Technical Bulletin No. 295,revised 2/02, Promega Corporation).

Further diseases or disorders associated with the proteasome includeaccelerated or enhanced proteolysis that occurs in atrophying muscles,such as is often associated with activation of a nonlysomalATP-requiring process involving ubiquitin. Accelerated or enhancedproteolysis can be the result of any of numerous causes includingsepsis, burns, trauma, cancer, infection, neurodegenerative diseasessuch as muscular dystrophy, acidosis, or spinal/nerve injuries,corticosteroid use, fever, stress, and starvation. Compounds of theinvention can be tested for inhibition of muscle wastage by any variousprocedures known in the art such as by measuring urinary excretion ofmodified amino acid 3-methylhistidine (see, e.g., Young, et al.,Federation Proc., 1978, 37, 229).

Compounds of the present invention can be further used to treat orprevent diseases or disorders associated with activity of NF-κBincluding for example, human immunodeficiency virus (HIV) infection andinflammatory disorders resulting from, for example, transplantationrejection, arthritis, infection, inflammatory bowel disease, asthma,osteoporosis, osteoarthritis, psoriasis, restenosis, and autoimmunediseases. Accordingly, a process that prevents activation of NF-κB inpatients suffering from such a disease would be therapeuticallybeneficial. Inhibition of the NF-κB activity can be measured by using aDNA binding assay such a described in Palombella, et al., Cell, 1994,78, 773.

Those of ordinary skill in the art can readily identify individuals whoare prone to or suspected of suffering from such diseases or disordersusing standard diagnostic techniques.

Example A Assay for Chymotrypsin-Like Activity of 20S Human ErythrocyteProteasome (HEP)

Proteasome chymotrypsin-like activity of compounds of the invention canbe assayed according to the following procedure.

In 96-well microtiter plates, 20S Human Erythrocyte Proteasome (HEP),purchased from Immatics Biotechnologies Inc., Tübingen, Germany can beplated at 0.2 μg/mL (about 0.6 nM catalytic sites) in 0.04% SDS 20 mMTris buffer. A fluorimetric substrate Suc-LLVY-AMC(succinyl-Leu-Leu-Val-Tyr-7-amido-4-methylcoumarin), purchased fromSigma Inc., St. Louis, Mo., USA can be added to a final concentration of100 μM from a stock solution of 10 mM in dimethylsulfoxide. Reactionvolumes can be 100 μl per well. After incubation for various periods oftime at 37° C., the concentration of free AMC (aminomethylcoumarin) canbe determined on a Perkin Elmer HTS 7000 Plus microplate reader,excitation 370 nM and emission 465 nM. Proteasome activity can bedetermined under conditions in which substrate hydrolysis increasedlinearly with time and the change in fluorescence signal is proportionalto the concentration of free AMC.

Example B Assay for Activity of α-1-Chymotrypsin

In 96-well microtiter plates bovine α-chymotrypsin, purchased from SigmaInc., can be plated at 10 ng/mL (about 2 μM catalytic sites) in 0.5 MNaCl 50 mM Hepes buffer. A fluorimetric substrate Suc-AAPF-AMC(succinyl-Ala-Ala-Pro-Phe-7-amido-4-methylcoumarin), purchased fromSigma Inc., St. Louis, Mo., USA can be added to a final concentration of25 μM from a stock solution of 10 mM in dimethylsulfoxide. Reactionvolumes are 100 μl per well. After incubation for various periods oftime at room temperature, the concentration of free AMC can bedetermined on a Perkin Elmer HTS 7000 Plus microplate reader, excitation370 nM and emission 465 nM. α-Chymotrypsin activity can be determinedunder conditions in which substrate hydrolysis increased linearly withtime and the change in fluorescence signal was proportional to theconcentration of free AMC.

Example C Determination of Ic₅₀ Values for HEP and α-ChymotrypsinInhibitors

IC₅₀ values are typically defined as the concentration of a compoundnecessary to produce 50% inhibition of the enzyme's activity. IC₅₀values are useful indicators of the activity of a compound for itsdesignated use. The proteasome inhibitors of the invention can beconsidered active if they have IC₅₀ values of less than about 1micromolar for inhibition of human erythrocyte proteasome (HEP). In someembodiments, the inhibitors show some specificity for HEP and the ratioof the IC₅₀ for inhibition of bovine α-chymotrypsin versus the IC₅₀ forinhibition of HEP, i.e, IC₅₀ (α-Chymotripsin)/IC₅₀ (HEP), is greaterthen about 100.

Inhibition of the chymotrypsin-like activity of HEP and of bovineα-chymotrypsin can be determined by incubating the enzyme with variousconcentrations of putative inhibitors for 15 minutes at 37° C. (or roomtemperature for α-chymotrypsin) prior to the addition of substrate. Eachexperimental condition can be evaluated in triplicate.

Compounds of the present invention are considered active in the aboveidentified assay if their IC₅₀ values for inhibition of HEP are lessthan 1000 nanoMolar. Preferably compounds of the present invention willhave IC₅₀ values for inhibition of HEP less than 100 nanoMolar. Morepreferably compounds of the present invention will have IC₅₀ values forinhibition of HEP less than 10 nanoMolar.

Example D Cellular Assay for Chymotrypsin-Like Activity of Proteasome inMolt-4 Cell Line

The chymotrypsin-like activity of proteasome in Molt-4 cells (humanleukemia) can be assayed according to the following procedure. A briefdescription of the method was published previously (Harding et al., J.Immunol., 1995, 155, 1767).

Molt-4 cells are washed and resuspended in HEPES-buffered Saline (5.4 mMKCl, 120 mM NaCl, 25 mM Glucose, 1.5 mM MgSO₄, 1 mM Na pyruvate, 20 mMHepes) and plated in 96-well microtiter white plates to a finalconcentration of 6×10⁶ cells/mL. Then various 5× proteasome inhibitorconcentrations (or diluted DMSO for controls), prepared from 250×DMSOsolutions by diluting 50-fold using HEPES-buffered saline, are added tothe plate to a final 1× concentration. After 15 minutes incubation at37° C., a fluorimetric cell permeable substrate (MeOSuc-FLF-AFC)(methoxysuccinyl-Phe-Leu-Phe-7-amido-4-trifluoromethylcoumarin)purchased from Enzyme Systems Products, catalogue number AFC-88, isadded to each well at a final concentration of 25 μM from a stocksolution of 20 mM in DMSO. Reaction volumes can be 100 μl per well.

The concentration of free AFC is monitored every 1.5 min for 30 min (22cycles) on a Polastar Optima, BMG Labtechnologies microplate reader,using an excitation wavelength of 390 nm and emission wavelength of 520nm. Proteasome activity can be determined under conditions in whichsubstrate hydrolysis increased linearly with time and the change influorescent signal is proportional to the concentration of free AFC.

Example E Determination of EC₅₀ Values for Proteasome Inhibitors inMOLT-4 Cell Line

EC₅₀ values are typically defined as the concentration of a compoundrequired to produce an inhibition of the enzyme's activity halfwaybetween the minimum and the maximum response (0% and 85-90% respectivelyfor this assay). EC₅₀ values are useful indicators of the activity of acompound for its designated use. The compounds of the invention can beconsidered active if they have an EC₅₀ of less than about 10 micromolar.

Inhibition of chymotrypsin-like activity of proteasome in Molt-4 cellsis determined by incubating cells with various concentrations ofputative inhibitors for 15 minutes at 37° C. prior to the addition ofsubstrate. Each experimental condition is evaluated in triplicate.

Compounds of the present invention are considered active in the aboveidentified assay if their EC₅₀ values for proteasome inhibition inMOLT-4 are less than 10 microMolar. Preferably compounds of the presentinvention will have EC₅₀ values for proteasome inhibition in MOLT-4 lessthan 2 microMolar. More preferably compounds of the present inventionwill have EC₅₀ values for proteasome inhibition in MOLT-4 less than 200nanomolar.

Example F Assay for Trypsin-Like Activity of the Proteasome

The trypsin-like activity of human proteasome can be assayed asdescribed above with the following modifications. Reactions can becarried out in Tris-glycerol buffer (pH 9.5) supplemented with 1 mM2-mercaptoethanol, and the substrate can be a fluorogenic substrate suchas benzyloxycarbonyl-Phe-Arg-AMC (100 μM).

After incubation for various periods of time at 37° C., theconcentration of free AMC can be determined on a Fluoroskan IIspectrofluorimeter with an excitation filter of 390 nm and an emissionfilter of 460 nm. Protease activity can be determined under conditionsin which substrate hydrolysis increases linearly with time and thechange in fluorescence is proportional to the concentration of free AMC.

Example G In Vivo Inhibition of Cellular Muscle Breakdown

The effect of inhibitors on the unweighting atrophy of the soleus musclein juvenile rats can be determined by, for example, the proceduresdescribed in Tischler, Metabolism, 1990, 39, 756. For example, juvenilefemale Sprague-Dawley rats (80-90 g) can be tail-cast, hind limbsuspended as described in Jaspers, et al., J. Appl. Physiol., 1984, 57,1472. The animal's hind limbs can be elevated above the floor of thecage with each animal housed individually. Animals can have free accessto food and water, and can be weighed at the time of suspension and attime of termination. During the suspension period the animals can bechecked daily to ensure that their toes are not touching the floor ofthe cage, and that there is no swelling of the tail due to the cast.

Experimental Design—Part 1

Each experiment can begin with the suspension of 20 rats which arerandomly divided into 4 groups of 5 animals each. Group A can besuspended for 2 days, providing baseline data to approximate the soleusmuscle size in other animals suspended for longer times. Average bodyweights for the groups at the outset of the study can be compared andused as a correction factor for body size differences. Group B can be asecond control group which has the soleus of one limb treated with anaqueous solution of mersalyl after two days of unweighting, todemonstrate the ability to slow muscle atrophy during unweighting, foreach group of animals. At 2 days after unweighting commences, an aqueoussolution of mersalyl (200 nM; 4 μL/100 g initial body wt) can beinjected into one soleus. The contralateral muscle can be injected witha similar volume of 0.9% saline (“Vehicle”). The animals can bemaintained under Innovar-vet (10 μL/100 g body wt) tranquilizationduring the in situ injection procedure. After the injections, theanimals can be suspended for an additional 24 hours and the soleus canbe removed. Groups C and D for each experiment can be used for testingeach of two different embodiments of the disclosed compounds. Animalscan be treated as in group B, except that 1 mM proteasome inhibitor,contained in dimethysulfoxide (DMSO), can be injected into the soleus ofone leg and DMSO only into the contralateral soleus. Thus eachexperiment consists of two control groups and the testing of proteasomeinhibitors of the invention. The completion of five such experimentswith different pairs of inhibitors provides for an “n” value of 10 fortesting each inhibitor and each can be tested in two different shipmentsof animals.

Processing of the Soleus Muscle—Part 1

After the animal is sacrificed, the soleus can be excised, trimmed offat and connective tissue, and carefully weighed. The muscle can thenhomogenized in 10% trichloroacetic acid (TCA) and the precipitatedprotein pelleted by centrifugation. The pellet can then be washed oncewith 10% TCA and once with ethanol:ether (1:1). The final pellet can besolubilized in 4 ml of 1N sodium hydroxide. The sample can be thenanalyzed for protein content by the biuret procedure, using albumin as astandard.

Data Analysis—Part 1

The effect of inhibitors on total muscle protein content can be examinedprimarily by paired comparison with the untreated contralateral muscle.The ratio of contents can be calculated and then analyzed statisticallyby analysis of variance (“ANOVA”). The left leg can always be thetreated leg so that the protein content ratios can be compared to thenon-treated control animals as well. In this way, a significantdifference can be shown by comparing the protein content of the twolegs, as well as the relative effectiveness of the tested inhibitors. Apaired student test can also be performed for the effect of eachseparate treatment. The non-treated control data also provide anestimate of protein content of day 2. This allows approximation of theprotein changes over the 24 hours of treatment for each of the Groups B,C, and D.

Experimental Design—Part 2

Each experiment can consist of 10 animals with groups of 5 animals beingtested with one of the inhibitors for its effect on protein synthesis.Control animals are not needed for this aspect of the study as thecontralateral DMSO-treated muscle serves as the paired control for theinhibitor-treated muscle. Each group can be injected as described forgroups C and D in part 1. Twenty-four hours after the in situ treatmentthe fractional rate of protein synthesis can be analyzed in both soleusmuscles. Each muscle can be injected with a 0.9% saline solution (3.5μl/100 g final body wt) containing ³H-phenylalanine (50 mM; 1μCi/^(m)l). Fifteen minutes later the middle two-thirds of the musclecan be excised and the muscle can be processed as described below.

Processing of the Soleus Muscle—Part 2

The muscle can be first washed for 10 minutes in 0.84% saline containing0.5 mM cycloheximide, to terminate protein synthesis, and 20 mMcycloleucine, to trap phenylalanine in the cell. The muscle can then behomogenized in 2.5 mL of ice-cold 2% perchloric acid. The precipitatedprotein can be pelleted by centrifugation. One aliquot of thesupernatant can be taken for liquid scintillation counting and anotheraliquot can be processed for conversion of phenylalanine tophenethylamine to determine the soluble phenylalanine concentrationfluorometrically. See, e.g., Garlick, et al., Biochem. J., 1980, 192,719. These values can provide the intracellular specific activity. Thespecific activity of phenylalanine in the muscle protein can bedetermined after hydrolyzing the protein by heating in 6N HCl. The aminoacids released can be solubilized in buffer. One aliquot can be takenfor scintillation counting and another for analysis of phenylalanine asfor the supernatant fraction. The fractional rate of protein synthesiscan be calculated as: protein specific activity/intracellular specificactivity x time.

Data Analysis—Part 2

Analyses of protein synthesis can be on a paired basis for eachinhibitor. Student paired t test comparisons of the contralateralmuscles can determine whether there is any effect of the inhibitor onprotein synthesis. Protein breakdown can be calculated approximately asthe fractional rate of protein synthesis (from part 2) plus thefractional rate of protein accretion (from part 1), where protein lossyields a negative value for protein accretion.

Qualitatively the ability of inhibitors to slow protein loss withoutaffecting protein synthesis indicates a slowing of protein degradation.

Example H In Vivo Investigation of Anti-Tumor Activity Materials

The proteasome inhibitors used for in vivo studies can be formulated inan appropriate medium for intravenous (iv) or oral (po) administration.For example, for the iv administration the compounds can be administereddissolved in 0.9% NaCl, or in mixtures of 0.9% NaCl, solutol HS15 anddimethylsulfoxide, for example in the ratio 87:10:3 (v:v:v),respectively.

Cell Lines

The following human and murine tumor cell lines of differenthistological origin can be used to test the antitumor activity of thecompounds of the invention: H460 (human, lung), A2780 (human, ovary),PC-3 (human, prostate), LoVo (human, colon), HCT116 (human, colon),BXPC3 (human, pancreatic), PANC-1 (human, pancreatic), MX-1 (human,mammary), MOLT (human, leukemia), multiple myeloma (human, myeloma), YC8(murine, lymphoma), L1210 (murine, leukemia), 3LL (murine, lung).

Animal Species

5-6 Weeks immunocompetent or immunodeprived mice are purchased fromcommercial sources, for example from Harlan (Correzzana, Mi Italy). CD1nu/nu mice are maintained under sterile conditions; sterilized cages,bedding, food and acidified water are used.

Tumor Cell Implantation and Growth

Solid tumor models of different hystotype (lung, ovary, breast,prostate, pancreatic, colon) can be transplanted subcutaneously (sc.)into the axillary region of immunocompetent mice (murine models) or inimmunodeprived mice (human models). Human tumor cell lines, originallyobtained from ATCC, can be adapted to grow “in vivo” as solid tumor from“in vitro culture”.

Hematological human or murine tumor models can be transplanted intodifferent sites (iv, ip, ic or sc) in immunocompetent mice (murinetumors) or in immunodeprived mice (human leukemia, lymphoma and myelomamodels), according to their highest tumor take.

Drug Treatment

Mice bearing solid (staged) or hematological tumors are randomized inexperimental groups (10 mice/group). For solid tumors, an average tumorweight of 80-100 mg for each group is considered to start the treatment;mice with the smallest and largest tumors are discarded.

Experimental groups are randomly assigned to the drug treatment and tothe control group. Animals can be treated iv or orally, depending on theoral bioavailability with the compounds following different treatmentschedules: iv weekly or twice weekly, or by daily oral administration.

On solid tumor models, drug treatment can begin when the tumor sizeranges between 80-100 mg after tumor transplantation (Day 0).

The compounds can be administered in a volume of 10 mL/Kg bodyweight/mouse in the appropriate solvent.

Parameters of Antitumor Activity

The following parameters can be assessed for the evaluation of theantitumor activity:

-   -   growth of primary solid tumor; in each mouse is monitored by        caliper measurement twice weekly;    -   survival time of treated mice as compared to control mice    -   twice weekly body weight evaluation of individual mice.

The tumor growth inhibition, TWI % (percentage of primary tumor growthinhibition in comparison with vehicle treated control groups) or theRelative tumor growth inhibition, RTWI % in case of staged tumors, isevaluated one week after the last drug treatment and the Tumor weight(TW) can be calculated as follows:

TW=½ab ²

where a and b are long and short diameters of the tumor mass in mm.

The antitumor activity can be determined as tumor weight inhibition (TWI%), which is calculated according to the formula:

${{TWI}\mspace{14mu} \%} = {100 - {\frac{{mean}\mspace{14mu} {TW}\mspace{14mu} {treated}}{{mean}\mspace{14mu} {TW}\mspace{14mu} {controls}} \times 100}}$

The RTWI % (relative percentage of primary tumor growth inhibition incomparison with vehicle treated control groups) is evaluated one weekafter the last drug treatment, according to the following formula:

${{RTWI}\mspace{14mu} \%} = {100 - {\frac{{mean}\mspace{14mu} {RV}\mspace{14mu} {of}\mspace{14mu} {treated}\mspace{14mu} {mice}}{{mean}\mspace{14mu} {RV}\mspace{14mu} {of}\mspace{14mu} {controls}\mspace{14mu} {mice}} \times 100\mspace{14mu} {where}}}$${RV} = \frac{{Vt}\mspace{14mu} \left( {{tumor}\mspace{14mu} {weight}\mspace{14mu} {on}\mspace{14mu} {day}\mspace{14mu} t} \right)}{{Vo}\mspace{14mu} \left( {{initial}\mspace{14mu} {tumor}\mspace{14mu} {weight}\mspace{14mu} {at}\mspace{14mu} {the}\mspace{14mu} {outset}\mspace{14mu} {of}\mspace{14mu} {treatment}} \right)}$

The Percent of Tumor Regression can be calculated as regressions interms of relative tumor weight, determined as tumor weight at given daydivided by initial tumor weight at the outset the experiment.

On haematological tumour models the antitumor activity can be determinedas percentage increase of the median survival time of mice expressed asthe ratio (T/C %) of the median survival time of the treated group (T)to that of the control group (C). Animals which are tumour-free at theend of the experiment (60 days after transplantation) are excluded fromthe calculation and considered as long term survivors (LTS).

Evaluation of Toxicity in Tumor Bearing Mice

Toxicity can be evaluated daily on the basis of the gross autopsyfindings and the weight loss. Mice are considered to have died oftoxicity when death occurs before the death of vehicle treated controlanimals, or when significant body weight loss (>20%), and/or spleen andliver size reduction are observed.

The BWC % (Body weight change %) is assessed as follow: 100−(mean bodyweight of mice at given day/mean body weight at start of treatment)×100.This value is determined one week after the last treatment with the testcompound.

Example K In Vitro Viability of Cells

The IC₅₀ values measuring in vitro viability of cells in the presence oftest compounds can be determined according to the following procedure.Cells can be seeded in 96-well plates at varying densities and thenassayed using the Calcein-AM viability assay after 24 hours to determinethe optimal final density for each cell type. Cells can then be seededin 96-well plates at the determined density in 100 μL of an appropriatecell media known to one skilled in the art.

Serial dilutions of test compounds can be made so that theconcentrations are twice the desired concentration to be evaluated. When100 μL of the dilution is then added to the cells plated in 100 μL ofmedia, a final concentration of, for example, 0, 11.7, 46.9, 187.5, 375,and 750 nM can be obtained. Compounds can be added to the plates threeto four hours after seeding the cells, then the plates can be incubatedat 37° C. for the desired time point (e.g., one, two, or three days).

Calcein-AM viability assays can be conducted at the desired time pointsas follows. Media can be aspirated using a manifold and metal plate toleave approximately 50 μL/well. The wells can be washed three times with200 μL DPBS, aspirating each time with the manifold to leave 50 μL/well.A 8 μM solution of Calcein-AM in DPBS can be prepared and 150 μL can beadded to each well. The plates can then be incubated at 37° C. for 30minutes. After incubation, calcein can be aspirated with the manifoldand cells can be washed with 200 μL DPBS as before. After finalaspiration, fluorescence can be measured using a Cytofluor 2300fluorescence plate reader. Negative controls can contain media and nocells, and experiments can be conducted in triplicate.

Example L Kinetic Experiments In Vitro

Compounds of the invention can be tested for proteasome inhibitoryactivity using a protocol described in Rock, et al., Cell, 1994, 78,761. According to this procedure, dissociation constants (K_(i)) for theequilibrium established when proteasome and test compound interact toform a complex. The reactions can be carried out using SDS-activated 20Sproteasome from rabbit muscle, and the proteasome substrate can beSuc-LLVY-AMC.

Example M Inhibition of Activation of NF-κB

Compounds of the invention can be tested for inhibiting the activity ofNF-κB by carrying out the assay described in Palombella, et al., Cell,1994, 78, 773). For example, MG63 osteocarcinoma cells can be stimulatedby treatment with TNF-α for designated times. Whole cell extracts can beprepared and analyzed by electrophoretic mobility shift assays using thePRDII probe from the human IFN-β gene promoter.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of Formula (I) can beadministered in the form of pharmaceutical compositions. Thesecompositions can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular, andintranasal, and can be prepared in a manner well known in thepharmaceutical art.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of Formula (I)above in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications. Anamount adequate to accomplish this is referred to as “therapeuticallyeffective amount.” Effective doses will depend on the disease conditionbeing treated as well as by the judgement of the attending cliniciandepending upon factors such as the severity of the disease, the age,weight and general condition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of inflammatory diseases, whichcomprise one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula(I). Such kits can further include, if desired, one or more of variousconventional pharmaceutical kit components, such as, for example,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference cited in the presentapplication, including patents, published patent applications, andjournal articles, is incorporated herein by reference in its entirety.

1. A method of treating cancer; accelerated or enhanced proteolysis;human immunodeficiency virus (HIV) infection; or inflammatory disorders;the method comprising: administering to a mammal having or predisposedto said cancer, proteolysis, disease, or disorder a therapeuticallyeffective amount of a compound of Formula (I)

or pharmaceutically acceptable salt form thereof, wherein: Q is—B(OR^(B))₂, boronic acid, attached via the boron atom, or a cyclicboronic ester attached via the boron atom, wherein said cyclic boronicester contains from 2 to 20 carbon atoms, and, optionally, a heteroatomwhich can be N, S, or O; R^(B) is, independently, H, C₁₋₄ alkyl,cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; Z is —CH(OH)CH₃ or—CH₂NR^(1a)R¹; Hy is a 5- or 6-membered heterocyclic group optionallyfused with an aryl or heteroaryl group, wherein said 5- or 6-memberedheterocyclic group contains at least one ring-forming N atom, andwherein said Hy is optionally substituted by 1, 2 or 3 R⁴; R¹ is H,C₁₋₁₀ alkyl, carbocyclyl, heterocyclyl, C₁₋₁₀ alkyl-C(═O)—, C₂₋₁₀alkenyl-C(═O)—, C₂₋₁₀ alkynyl-C(═O)—, carbocyclyl-C(═O)—,heterocyclyl-C(═O)—, carbocyclylalkyl-C(═O)—, heterocyclylalkyl-C(═O)—,C₁₋₁₀ alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocyclyl-S(═O)₂—,carbocyclylalkyl-S(═O)₂—, heterocyclylalkyl-S(═O)₂—, C₁-C₁₀alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocyclyl-NHC(═O)—,carbocyclylalkyl-NHC(═O)—, heterocyclylalkyl-NHC(═O)—, C₁-C₁₀alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocyclyl-OC(═O)—,carbocyclylalkyl-OC(═O)—, heterocyclylalkyl-OC(═O)—, C₁₋₁₀alkyl-NH—C(═O)—NHS(═O)₂—, carbocyclyl-NH—C(═O)—NHS(═O)₂—,heterocyclyl-NH—C(═O)—NHS(═O)₂—, C₁₋₁₀ alkyl-S(═O)₂—NH—C(═O)—,carbocyclyl-S(═O)₂—NH—C(═O)—, heterocyclyl-S(═O)₂—NH—C(═O)—, or an aminoprotecting group; wherein R¹ is optionally substituted with 1, 2 or 3substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, F,Cl, Br, I, C₁₋₄ haloalkyl, —NH₂, —NHR², —N(R²)₂, —N₃, —NO₂, —CN, —CNO,—CNS, —C(═O)OR², —C(═O)R², —OC(═O)R², —N(R²)C(═O)R², —N(R²)C(═O)OR²,—C(═O)N(R²)₂, ureido, —OR², —SR², —S(═O)—(C₁₋₆ alkyl), —S(═O)₂—(C₁₋₆alkyl), —S(═O)-aryl, —S(═O)₂-aryl, —S(═O)₂—N(R²)₂; carbocyclyloptionally substituted with 1, 2, 3, 4 or 5 R³; and heterocyclyloptionally substituted with 1, 2, 3, 4, or 5 R³; R^(1a) is H.Alternatively, R^(1a) and R¹ together with the N atom to which they areattached form a 4-, 5-, 6- or 7-membered heterocyclyl group optionallysubstituted with 1, 2, or 3 R³; R² is, independently, H or C₁₋₆ alkyl;alternatively, two R² may be combined, together with the N atom to whichthey are attached, to form a 5-, 6- or 7-membered heterocyclic group; R³is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—; R⁴ is, independently, selected from C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, —OR^(4a), —SR^(4a), —CN, halo, haloalkyl, —NH₂,—NH(alkyl), —N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —COOH,—C(═O)O-alkyl, —C(═O)alkyl, —C(O)H, —S(═O)-alkyl, —S(═O)₂-alkyl,—S(═O)-aryl, —S(═O)₂-aryl, carbocyclyl optionally substituted with 1, 2or 3 R⁵, and heterocyclyl optionally substituted with 1, 2 or 3 R⁵;R^(4a) is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, carbocyclylor heterocyclyl; R⁵ is, independently, selected from C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy,amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—,aryl-OC(═O)—, alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—,alkyl-C(═O)O—, —OH, —SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—,alkyl-S(═O)₂—, H₂NS(═O)—, and H₂NS(═O)₂—; with the proviso that when Zis —CH(OH)CH₃ and Q is

then Hy is other than


2. The method of claim 1, wherein the method is a method of treatingcancer.
 3. The method of claim 2, wherein said cancer is selected fromthe group consisting of skin, prostate, colorectal, pancreas, kidney,ovary, mammary, liver, tongue, lung, smooth muscle tissue, leukemia,lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.
 3. Themethod of claim 1, wherein the method is a method of treatingaccelerated or enhanced proteolysis.
 4. The method of claim 1, whereinthe method is a method of treating human immunodeficiency virus (HIV)infection.
 5. The method of claim 1, wherein the method is a method oftreating inflammatory disorders.
 6. The method of claim 5, wherein theinflammatory disorders result from transplantation rejection, arthritis,infection, inflammatory bowel disease, asthma, osteoporosis,osteoarthritis, psoriasis, restenosis, or autoimmune diseases.
 7. Themethod of claim 1, wherein the compound of Formula (I) is administeredin combination with one or more antitumor or anticancer agent and/orradiotherapy.
 8. The method of claim 2, wherein the compound of Formula(I) is administered in combination with one or more antitumor oranticancer agent and/or radiotherapy.
 9. The method of claim 3, whereinthe compound of Formula (I) is administered in combination with one ormore antitumor or anticancer agent and/or radiotherapy.
 10. A method ofinhibiting the degradation of a protein comprising contacting proteasomecapable of degrading said protein with a compound of Formula (I)

or pharmaceutically acceptable salt form thereof, wherein: Q is—B(OR^(B))₂, boronic acid, attached via the boron atom, or a cyclicboronic ester attached via the boron atom, wherein said cyclic boronicester contains from 2 to 20 carbon atoms, and, optionally, a heteroatomwhich can be N, S, or O; R^(B) is, independently, H, C₁₋₄ alkyl,cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; Z is —CH(OH)CH₃ or—CH₂NR^(1a)R¹; Hy is a 5- or 6-membered heterocyclic group optionallyfused with an aryl or heteroaryl group, wherein said 5- or 6-memberedheterocyclic group contains at least one ring-forming N atom, andwherein said Hy is optionally substituted by 1, 2 or 3 R⁴; R¹ is H,C₁₋₁₀ alkyl, carbocyclyl, heterocyclyl, C₁₋₁₀ alkyl-C(═O)—, C₂₋₁₀alkenyl-C(═O)—, C₂₋₁₀ alkynyl-C(═O)—, carbocyclyl-C(═O)—,heterocyclyl-C(═O)—, carbocyclylalkyl-C(═O)—, heterocyclylalkyl-C(═O)—,C₁₋₁₀ alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocyclyl-S(═O)₂—,carbocyclylalkyl-S(═O)₂—, heterocyclylalkyl-S(═O)₂—, C₁-C₁₀alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocyclyl-NHC(═O)—,carbocyclylalkyl-NHC(═O)—, heterocyclylalkyl-NHC(═O)—, C₁-C₁₀alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocyclyl-OC(═O)—,carbocyclylalkyl-OC(═O)—, heterocyclylalkyl-OC(═O)—, C₁₋₁₀alkyl-NH—C(═O)—NHS(═O)₂—, carbocyclyl-NH—C(═O)—NHS(═O)₂—,heterocyclyl-NH—C(═O)—NHS(═O)₂—, C₁₋₁₀ alkyl-S(═O)₂—NH—C(═O)—,carbocyclyl-S(═O)₂—NH—C(═O)—, heterocyclyl-S(═O)₂—NH—C(═O)—, or an aminoprotecting group; wherein R¹ is optionally substituted with 1, 2 or 3substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, F,Cl, Br, I, C₁₋₄ haloalkyl, —NH₂, —NHR², —N(R²)₂, —N₃, —NO₂, —CN, —CNO,—CNS, —C(═O)OR², —C(═O)R², —OC(═O)R², —N(R²)C(═O)R², —N(R²)C(═O)OR²,—C(═O)N(R²)₂, ureido, —OR², —SR², —S(═O)—(C₁₋₆ alkyl), —S(═O)₂—(C₁₋₆alkyl), —S(═O)-aryl, —S(═O)₂-aryl, —S(═O)₂—N(R²)₂; carbocyclyloptionally substituted with 1, 2, 3, 4 or 5 R³; and heterocyclyloptionally substituted with 1, 2, 3, 4, or 5 R³; R^(1a) is H.Alternatively, R^(1a) and R¹ together with the N atom to which they areattached form a 4-, 5-, 6- or 7-membered heterocyclyl group optionallysubstituted with 1, 2, or 3 R³; R² is, independently, H or C₁₋₆ alkyl;alternatively, two R² may be combined, together with the N atom to whichthey are attached, to form a 5-, 6- or 7-membered heterocyclic group; R³is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—; R⁴ is, independently, selected from C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, —OR^(4a), SR^(4a), —CN, halo, haloalkyl, —NH₂,—NH(alkyl), —N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —COOH,—C(═O)O-alkyl, —C(═O)alkyl, —C(O)H, —S(═O)-alkyl, —S(═O)₂-alkyl,—S(═O)-aryl, —S(═O)₂-aryl, carbocyclyl optionally substituted with 1, 2or 3 R⁵, and heterocyclyl optionally substituted with 1, 2 or 3 R⁵;R^(4a) is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, carbocyclylor heterocyclyl; R⁵ is, independently, selected from C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy,amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—,aryl-OC(═O)—, alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—,alkyl-C(═O)O—, —OH, —SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—,alkyl-S(═O)₂—, H₂NS(═O)—, and H₂NS(═O)₂—; with the proviso that when Zis —CH(OH)CH₃ and Q is

then Hy is other than


11. The method of claim 8 wherein said protein is marked with ubiquitin.12. The method of claim 8 wherein said protein is p53.
 13. A method ofinhibiting activity of transcription factor NF-κB comprising contactingIκB, the inhibitor of transcription factor NF-κB, with a compound ofFormula (I)

or pharmaceutically acceptable salt form thereof, wherein: Q is—B(OR^(B))₂, boronic acid, attached via the boron atom, or a cyclicboronic ester attached via the boron atom, wherein said cyclic boronicester contains from 2 to 20 carbon atoms, and, optionally, a heteroatomwhich can be N, S, or O; R^(B) is, independently, H, C₁₋₄ alkyl,cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; Z is —CH(OH)CH₃ or—CH₂NR^(1a)R¹; Hy is a 5- or 6-membered heterocyclic group optionallyfused with an aryl or heteroaryl group, wherein said 5- or 6-memberedheterocyclic group contains at least one ring-forming N atom, andwherein said Hy is optionally substituted by 1, 2 or 3 R⁴; R¹ is H,C₁₋₁₀ alkyl, carbocyclyl, heterocyclyl, C₁₋₁₀ alkyl-C(═O)—, C₂₋₁₀alkenyl-C(═O)—, C₂₋₁₀ alkynyl-C(═O)—, carbocyclyl-C(═O)—,heterocyclyl-C(═O)—, carbocyclylalkyl-C(═O)—, heterocyclylalkyl-C(═O)—,C₁₋₁₀ alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocyclyl-S(═O)₂—,carbocyclylalkyl-S(═O)₂—, heterocyclylalkyl-S(═O)₂—, C₁-C₁₀alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocyclyl-NHC(═O)—,carbocyclylalkyl-NHC(═O)—, heterocyclylalkyl-NHC(═O)—, C₁-C₁₀alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocyclyl-OC(═O)—,carbocyclylalkyl-OC(═O)—, heterocyclylalkyl-OC(═O)—, C₁₋₁₀alkyl-NH—C(═O)—NHS(═O)₂—, carbocyclyl-NH—C(═O)—NHS(═O)₂—,heterocyclyl-NH—C(═O)—NHS(═O)₂—, C₁₋₁₀ alkyl-S(═O)₂—NH—C(═O)—,carbocyclyl-S(═O)₂—NH—C(═O)—, heterocyclyl-S(═O)₂—NH—C(═O)—, or an aminoprotecting group; wherein R¹ is optionally substituted with 1, 2 or 3substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, F,Cl, Br, I, C₁₋₄ haloalkyl, —NH₂, —NHR², —N(R²)₂, —N₃, —NO₂, —CN, —CNO,—CNS, —C(═O)OR², —C(═O)R², —OC(═O)R², —N(R²)C(═O)R², —N(R²)C(═O)OR²,—C(═O)N(R²)₂, ureido, —OR², —SR², —S(═O)—(C₁₋₆ alkyl), —S(═O)₂—(C₁₋₆alkyl), —S(═O)-aryl, —S(═O)₂-aryl, —S(═O)₂—N(R²)₂; carbocyclyloptionally substituted with 1, 2, 3, 4 or 5 R³; and heterocyclyloptionally substituted with 1, 2, 3, 4, or 5 R³; R^(1a) is H.Alternatively, R^(1a) and R¹ together with the N atom to which they areattached form a 4-, 5-, 6- or 7-membered heterocyclyl group optionallysubstituted with 1, 2, or 3 R³; R² is, independently, H or C₁₋₆ alkyl;alternatively, two R² may be combined, together with the N atom to whichthey are attached, to form a 5-, 6- or 7-membered heterocyclic group; R³is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, —OH,—SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, andH₂NS(═O)₂—; R⁴ is, independently, selected from C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, —OR^(4a), SR^(4a), —CN, halo, haloalkyl, —NH₂,—NH(alkyl), —N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —COOH,—C(═O)O-alkyl, —C(═O)alkyl, —C(O)H, —S(═O)-alkyl, —S(═O)₂-alkyl,—S(═O)-aryl, —S(═O)₂-aryl, carbocyclyl optionally substituted with 1, 2or 3 R⁵, and heterocyclyl optionally substituted with 1, 2 or 3 R⁵;R^(4a) is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, carbocyclylor heterocyclyl; R⁵ is, independently, selected from C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy,amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—,aryl-OC(═O)—, alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—,alkyl-C(═O)O—, —OH, —SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—,alkyl-S(═O)₂—, H₂NS(═O)—, and H₂NS(═O)₂—; with the proviso that when Zis —CH(OH)CH₃ and Q is

then Hy is other than